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17-892 S038 FDA approved labeling text 2.11.08
1
Halcion®
triazolam tablets, USP CIV
DESCRIPTION
HALCION Tablets contain triazolam, a triazolobenzodiazepine hypnotic agent.
Triazolam is a white crystalline powder, soluble in alcohol and poorly soluble in water. It has a molecular
weight of 343.21.
The chemical name for triazolam is 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[4,3-α] [1,4]
benzodiazepine.
The structural formula is represented below:
Each HALCION Tablet, for oral administration, contains 0.125 mg or 0.25 mg of triazolam. Inactive
ingredients: 0.125 mg—cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon
dioxide, sodium benzoate; 0.25 mg—cellulose, corn starch, docusate sodium, FD&C Blue No. 2, lactose,
magnesium stearate, silicon dioxide, sodium benzoate.
CLINICAL PHARMACOLOGY
Triazolam is a hypnotic with a short mean plasma half-life reported to be in the range of
1.5 to 5.5 hours. In normal subjects treated for 7 days with four times the recommended dosage, there was no
evidence of altered systemic bioavailability, rate of elimination, or accumulation. Peak plasma levels are
reached within 2 hours following oral administration. Following recommended doses of HALCION,
triazolam peak plasma levels in the range of 1 to 6 ng/mL are seen. The plasma levels achieved are
proportional to the dose given.
Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are
excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two
primary metabolites accounted for 79.9% of urinary excretion. Urinary excretion appeared to be biphasic in
its time course.
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17-892 S038 FDA approved labeling text 2.11.08
2
HALCION Tablets 0.5 mg, in two separate studies, did not affect the prothrombin times or plasma warfarin
levels in male volunteers administered sodium warfarin orally.
Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro.
Triazolam 14C was administered orally to pregnant mice. Drug-related material appeared uniformly
distributed in the fetus with 14C concentrations approximately the same as in the brain of the mother.
In sleep laboratory studies, HALCION Tablets significantly decreased sleep latency, increased the duration
of sleep, and decreased the number of nocturnal awakenings. After 2 weeks of consecutive nightly
administration, the drug’s effect on total wake time is decreased, and the values recorded in the last third of
the night approach baseline levels. On the first and/or second night after drug discontinuance (first or second
post-drug night), total time asleep, percentage of time spent sleeping, and rapidity of falling asleep frequently
were significantly less than on baseline (predrug) nights. This effect is often called "rebound" insomnia.
The type and duration of hypnotic effects and the profile of unwanted effects during administration of
benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active
metabolites formed. When half-lives are long, the drug or metabolites may accumulate during periods of
nightly administration and be associated with impairments of cognitive and motor performance during
waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In
contrast, if half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and
carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However,
during nightly use for an extended period pharmacodynamic tolerance or adaptation to some effects of
benzodiazepine hypnotics may develop. If the drug has a short half-life of elimination, it is possible that a
relative deficiency of the drug or its active metabolites (ie, in relationship to the receptor site) may occur at
some point in the interval between each night’s use. This sequence of events may account for two clinical
findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics:
1) increased wakefulness during the last third of the night and 2) the appearance of increased daytime anxiety
after 10 days of continuous treatment.
In a study of elderly (62–83 years old) versus younger subjects (21–41 years old) who received HALCION at
the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment
of psychomotor performance. These effects resulted largely from higher plasma concentrations of triazolam
in the elderly.
INDICATIONS AND USAGE
HALCION is indicated for the short-term treatment of insomnia (generally 7–10 days). Use for more than 2–
3 weeks requires complete reevaluation of the patient (see WARNINGS).
Prescriptions for HALCION should be written for short-term use (7–10 days) and it should not be prescribed
in quantities exceeding a 1-month supply.
CONTRAINDICATIONS
HALCION Tablets are contraindicated in patients with known hypersensitivity to this drug or other
benzodiazepines.
Benzodiazepines may cause fetal damage when administered during pregnancy. An increased risk of
congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester
of pregnancy has been suggested in several studies. Transplacental distribution has resulted in neonatal CNS
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17-892 S038 FDA approved labeling text 2.11.08
3
depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks
of pregnancy.
HALCION is contraindicated in pregnant women. If there is a likelihood of the patient becoming pregnant
while receiving HALCION, she should be warned of the potential risk to the fetus. Patients should be
instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing
potential may be pregnant at the time of institution of therapy should be considered.
HALCION is contraindicated with ketoconazole, itraconazole, and nefazodone, medications that
significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) (see
WARNINGS and PRECAUTIONS–Drug Interactions).
WARNINGS
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder,
symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The
failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary
psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of
new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical
disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Because
some of the important adverse effects of sedative-hypnotics appear to be dose related (see Precautions and
Dosage and Administration), it is important to use the smallest possible effective dose, especially in the
elderly.
Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-
hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve
as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur
with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with
sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at
doses exceeding the maximum recommended dose. Due to the risk to the patient and the community,
discontinuation of sedative-hypnotics should be strongly considered for patients who report a “sleep-driving”
episode.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been
reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients
usually do not remember these events.
Severe anaphylactic and anaphylactoid reactions
Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking
the first or subsequent doses of sedative-hypnotics, including Halcion. Some patients have had additional
symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients
have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or
larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with
Halcion should not be rechallenged with the drug.
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17-892 S038 FDA approved labeling text 2.11.08
4
Central nervous system manifestations
An increase in daytime anxiety has been reported for HALCION after as few as 10 days of continuous use.
In some patients this may be a manifestation of interdose withdrawal (see CLINICAL PHARMACOLOGY).
If increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable.
A variety of abnormal thinking and behavior changes have been reported to occur in association with the use
of benzodiazepine hypnotics including HALCION. Some of these changes may be characterized by
decreased inhibition, eg, aggressiveness and extroversion that seem excessive, similar to that seen with
alcohol and other CNS depressants (eg, sedative/hypnotics). Other kinds of behavioral changes have also
been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily
depressed patients, the worsening of depression, including suicidal thinking, has been reported in association
with the use of benzodiazepines.
It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed
above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder.
Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and
immediate evaluation.
Because of its depressant CNS effects, patients receiving triazolam should be cautioned against engaging in
hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor
vehicle. For the same reason, patients should be cautioned about the concomitant ingestion of alcohol and
other CNS depressant drugs during treatment with HALCION Tablets.
As with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical
reactions have been reported following therapeutic doses of HALCION. Data from several sources suggest
that anterograde amnesia may occur at a higher rate with HALCION than with other benzodiazepine
hypnotics.
Triazolam interaction with drugs that inhibit metabolism via cytochrome P450 3A:
The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A).
Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of triazolam.
Consequently, triazolam should be avoided in patients receiving very potent inhibitors of CYP 3A. With
drugs inhibiting CYP 3A to a lesser but still significant degree, triazolam should be used only with caution
and consideration of appropriate dosage reduction. For some drugs, an interaction with triazolam has been
quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience
with similar drugs in the same pharmacologic class.
The following are examples of drugs known to inhibit the metabolism of triazolam and/or related
benzodiazepines, presumably through inhibition of CYP 3A.
Potent CYP 3A inhibitors: Potent inhibitors of CYP 3A that should not be used concomitantly with
triazolam include ketoconazole, itraconazole, and nefazodone. Although data concerning the effects of azole-
type antifungal agents other than ketoconazole and itraconazole on triazolam metabolism are not available,
they should be considered potent CYP 3A inhibitors, and their coadministration with triazolam is not
recommended (see CONTRAINDICATIONS).
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving triazolam (caution
and consideration of dose reduction are recommended during coadministration with triazolam):
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17-892 S038 FDA approved labeling text 2.11.08
5
Macrolide Antibiotics—Coadministration of erythromycin increased the maximum plasma concentration of
triazolam by 46%, decreased clearance by 53%, and increased half-life by 35%; caution and consideration of
appropriate triazolam dose reduction are recommended. Similar caution should be observed during
coadministration with clarithromycin and other macrolide antibiotics.
Cimetidine—Coadministration of cimetidine increased the maximum plasma concentration of triazolam by
51%, decreased clearance by 55%, and increased half-life by 68%; caution and consideration of appropriate
triazolam dose reduction are recommended.
Other drugs possibly affecting triazolam metabolism: Other drugs possibly affecting triazolam metabolism
by inhibition of CYP 3A are discussed in the PRECAUTIONS section (see PRECAUTIONS–Drug
Interactions).
PRECAUTIONS
General: In elderly and/or debilitated patients it is recommended that treatment with HALCION Tablets be
initiated at 0.125 mg to decrease the possibility of development of oversedation, dizziness, or impaired
coordination.
Some side effects reported in association with the use of HALCION appear to be dose related. These include
drowsiness, dizziness, light-headedness, and amnesia.
The relationship between dose and what may be more serious behavioral phenomena is less certain.
Specifically, some evidence, based on spontaneous marketing reports, suggests that confusion, bizarre or
abnormal behavior, agitation, and hallucinations may also be dose related, but this evidence is inconclusive.
In accordance with good medical practice it is recommended that therapy be initiated at the lowest effective
dose (see DOSAGE AND ADMINISTRATION).
Cases of "traveler’s amnesia" have been reported by individuals who have taken HALCION to induce sleep
while traveling, such as during an airplane flight. In some of these cases, insufficient time was allowed for
the sleep period prior to awakening and before beginning activity. Also, the concomitant use of alcohol may
have been a factor in some cases.
Caution should be exercised if HALCION is prescribed to patients with signs or symptoms of depression that
could be intensified by hypnotic drugs. Suicidal tendencies may be present in such patients and protective
measures may be required. Intentional over-dosage is more common in these patients, and the least amount
of drug that is feasible should be available to the patient at any one time.
The usual precautions should be observed in patients with impaired renal or hepatic function, chronic
pulmonary insufficiency, and sleep apnea. In patients with compromised respiratory function, respiratory
depression and apnea have been reported infrequently.
Information for patients: The text of a Medication Guide for patients is included at the end of this insert.
To assure safe and effective use of HALCION, the information and instructions provided in this Medication
Guide should be discussed with patients.
“Sleep-driving” and other complex behaviors:
There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars
while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should
be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more
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17-892 S038 FDA approved labeling text 2.11.08
6
likely to occur when sedative-hypnotics are taken with alcohol or other central nervous system depressants
(see WARNINGS). Other complex behaviors (e.g., preparing and eating food, making phone calls, or having
sex) have been reported in patients who are not fully awake after taking a sedative hypnotic. As with sleep-
driving, patients usually do not remember these events.
Laboratory tests: Laboratory tests are not ordinarily required in otherwise healthy patients.
Drug interactions: Both pharmacodynamic and pharmacokinetic interactions have been reported with
benzodiazepines. In particular, triazolam produces additive CNS depressant effects when coadministered
with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which
themselves produce CNS depression.
Drugs that inhibit triazolam metabolism via cytochrome P450 3A: The initial step in triazolam metabolism
is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this metabolic pathway
may have a profound effect on the clearance of triazolam (see CONTRAINDICATIONS and WARNINGS
for additional drugs of this type). Halcion is contraindicated with ketoconzaole, itraconazole, and
nefazodone.
Drugs and other substances demonstrated to be CYP 3A inhibitors of possible clinical significance on the
basis of clinical studies involving triazolam (caution is recommended during coadministration with
triazolam):
Isoniazid—Coadministration of isoniazid increased the maximum plasma concentration of triazolam by
20%, decreased clearance by 42%, and increased half-life by 31%.
Oral contraceptives—Coadministration of oral contraceptives increased maximum plasma concentration by
6%, decreased clearance by 32%, and increased half-life by 16%.
Grapefruit juice—Coadministration of grapefruit juice increased the maximum plasma concentration of
triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%.
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines
metabolized similarly to triazolam or on the basis of in vitro studies with triazolam or other
benzodiazepines (caution is recommended during coadministration with triazolam): Available data from
clinical studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for
the following: fluvoxamine, diltiazem, and verapamil. Data from in vitro studies of triazolam suggest a
possible drug interaction with triazolam for the following: sertraline and paroxetine. Data from in vitro
studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the
following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended
during coadministration of any of these drugs with triazolam (see WARNINGS).
Drugs that affect triazolam pharmacokinetics by other mechanisms:
Ranitidine—Coadministration of ranitidine increased the maximum plasma concentration of triazolam by
30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. Caution is
recommended during coadministration with triazolam.
Carcinogenesis, mutagenesis, impairment of fertility: No evidence of carcinogenic potential was observed
in mice during a 24-month study with HALCION in doses up to 4,000 times the human dose.
Pregnancy:
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17-892 S038 FDA approved labeling text 2.11.08
7
1. Teratogenic effects: Pregnancy category X (see CONTRAINDICATIONS).
2. Non-teratogenic effects: It is to be considered that the child born of a mother who is on benzodiazepines
may be at some risk for withdrawal symptoms from the drug, during the postnatal period. Also, neonatal
flaccidity has been reported in an infant born of a mother who had been receiving benzodiazepines.
Nursing mothers: Human studies have not been performed; however, studies in rats have indicated that
HALCION and its metabolites are secreted in milk. Therefore, administration of HALCION to nursing
mothers is not recommended.
Pediatric use: Safety and effectiveness of HALCION in individuals below 18 years of age have not been
established.
Geriatric use: The elderly are especially susceptible to the dose related adverse effects of HALCION. They
exhibit higher plasma triazolam concentrations due to reduced clearance of the drug as compared with
younger subjects at the same dose. To minimize the possibility of development of oversedation, the smallest
effective dose should be used (see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS, and
DOSAGE AND ADMINISTRATION).
Tolerance/Withdrawal Phenomena
Some loss of effectiveness or adaptation to the sleep inducing effects of these medications may develop after
nightly use for more than a few weeks and there may be a degree of dependence that develops. For the
benzodiazepine sleeping pills that are eliminated quickly from the body, a relative deficiency of the drug
may occur at some point in the interval between each night’s use. This can lead to (1) increased wakefulness
during the last third of the night, and (2) the appearance of increased signs of daytime anxiety or
nervousness. These two events have been reported in particular for HALCION.
There can be more severe ‘withdrawal’ effects when a benzodiazepine sleeping pill is stopped. Such effects
can occur after discontinuing these drugs following use for only a week or two, but may be more common
and more severe after longer periods of continuous use. One type of withdrawal phenomenon is the
occurrence of what is known as ‘rebound insomnia’. That is, on the first few nights after the drug is stopped,
insomnia is actually worse than before the sleeping pill was given. Other withdrawal phenomena following
abrupt stopping of benzodiazepine sleeping pills range from mild unpleasant feelings to a major withdrawal
syndrome which may include abdominal and muscle cramps, vomiting, sweating, tremor, and rarely,
convulsions.
ADVERSE REACTIONS
During placebo-controlled clinical studies in which 1,003 patients received HALCION Tablets, the most
troublesome side effects were extensions of the pharmacologic activity of triazolam, eg, drowsiness,
dizziness, or light-headedness.
The figures cited below are estimates of untoward clinical event incidence among subjects who participated
in the relatively short duration (i.e., 1 to 42 days) placebo-controlled clinical trials of HALCION. The figures
cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice
where patient characteristics and other factors often differ from those in clinical trials. These figures cannot
be compared with those obtained from other clinical studies involving related drug products and placebo, as
each group of drug trials is conducted under a different set of conditions.
Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the
relative contributions of drug and nondrug factors to the untoward event incidence rate in the population
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17-892 S038 FDA approved labeling text 2.11.08
8
studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient while
inducing it in others. (For example, an anticholinergic, anxiolytic drug may relieve dry mouth [a sign of
anxiety] in some subjects but induce it [an untoward event] in others.)
HALCION
PLACEBO
Number of Patients
1003
997
% Patients Reporting:
Central Nervous System
Drowsiness
14.0
6.4
Headache
9.7
8.4
Dizziness
7.8
3.1
Nervousness
5.2
4.5
Light-headedness
4.9
0.9
Coordination disorders/ataxia
4.6
0.8
Gastrointestinal
Nausea/vomiting
4.6
3.7
In addition to the relatively common (i.e., 1% or greater) untoward events enumerated above, the following
adverse events have been reported less frequently (i.e., 0.9% to0.5%): euphoria, tachycardia, tiredness,
confusional states/memory impairment, cramps/pain, depression, visual disturbances.
Rare (i.e., less than 0.5%) adverse reactions included constipation, taste alterations, diarrhea, dry mouth,
dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion,
death from hepatic failure in a patient also receiving diuretic drugs.
In addition to these untoward events for which estimates of incidence are available, the following adverse
events have been reported in association with the use of HALCION and other benzodiazepines: amnestic
symptoms (anterograde amnesia with appropriate or inappropriate behavior), confusional states
(disorientation, derealization, depersonalization, and/or clouding of consciousness), dystonia, anorexia,
fatigue, sedation, slurred speech, jaundice, pruritus, dysarthria, changes in libido, menstrual irregularities,
incontinence, and urinary retention. Other factors may contribute to some of these reactions, eg, concomitant
intake of alcohol or other drugs, sleep deprivation, an abnormal premorbid state, etc.
Other events reported include: paradoxical reactions such as stimulation, mania, an agitational state
(restlessness, irritability, and excitation), increased muscle spasticity, sleep disturbances, hallucinations,
delusions, aggressiveness, falling, somnambulism, syncope, inappropriate behavior and other adverse
behavioral effects. Should these occur, use of the drug should be discontinued.
The following events have also been reported: chest pain, burning tongue/glossitis/stomatitis.
Laboratory analyses were performed on all patients participating in the clinical program for HALCION. The
following incidences of abnormalities were observed in patients receiving HALCION and the corresponding
placebo group. None of these changes were considered to be of physiological significance.
HALCION
PLACEBO
Number of Patients
380
361
% of Patients Reporting:
Low
High
Low
High
Hematology
Hematocrit
*
*
*
*
Hemoglobin
*
*
*
*
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17-892 S038 FDA approved labeling text 2.11.08
9
Total WBC count
1.7
2.1
*
1.3
Neutrophil count
1.5
1.5
3.3
1.0
Lymphocyte count
2.3
4.0
3.1
3.8
Monocyte count
3.6
*
4.4
1.5
Eosinophil count
10.2
3.2
9.8
3.4
Basophil count
1.7
2.1
*
1.8
Urinalysis
Albumi
—
1.1
—
*
Sugar
—
*
—
*
RBC/HPF
—
2.9
—
2.9
WBC/HPF
—
11.7
—
7.9
Blood chemistry
Creatinine
2.4
1.9
3.6
1.5
Bilirubin
*
1.5
1.0
*
SGOT
*
5.3
*
4.5
Alkaline phosphatase
*
2.2
*
2.6
*Less than 1%
When treatment with HALCION is protracted, periodic blood counts, urinalysis, and blood chemistry
analyses are advisable.
Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during
therapy with HALCION and are of no known significance.
DRUG ABUSE AND DEPENDENCE
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is
characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive
substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal
syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug
and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces
changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to
both the desired and undesired effects of drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental
factors influencing its development and manifestations. It is characterized by behaviors that include one or
more of the following: impaired control over drug use, compulsive use, continued use despite harm, and
craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
Controlled Substance: Triazolam is a controlled substance under the Controlled Substance Act, and
HALCION Tablets have been assigned to Schedule IV.
Abuse, Dependence and Withdrawal: Withdrawal symptoms, similar in character to those noted with
barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria,
perceptual disturbances and insomnia), have occurred following abrupt discontinuance of benzodiazepines,
including HALCION. The more severe symptoms are usually associated with higher dosages and longer
usage, although patients at therapeutic dosages given for as few as 1–2 weeks can also have withdrawal
symptoms and in some patients there may be withdrawal symptoms (daytime anxiety, agitation) between
nightly doses (see CLINICAL PHARMACOLOGY). Consequently, abrupt discontinuation should be
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10
avoided and a gradual dosage tapering schedule is recommended in any patient taking more than the lowest
dose for more than a few weeks. The recommendation for tapering is particularly important in any patient
with a history of seizure.
The risk of dependence is increased in patients with a history of alcoholism, drug abuse, or in patients with
marked personality disorders. Such dependence-prone individuals should be under careful surveillance when
receiving HALCION. As with all hypnotics, repeat prescriptions should be limited to those who are under
medical supervision.
OVERDOSAGE
Because of the potency of triazolam, some manifestations of overdosage may occur at 2 mg, four times the
maximum recommended therapeutic dose (0.5 mg).
Manifestations of overdosage with HALCION Tablets include somnolence, confusion, impaired
coordination, slurred speech, and ultimately, coma. Respiratory depression and apnea have been reported
with overdosages of HALCION. Seizures have occasionally been reported after overdosages.
Death has been reported in association with overdoses of triazolam by itself, as it has with other
benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a
combination of a single benzodiazepine, including triazolam, and alcohol; benzodiazepine and alcohol levels
seen in some of these cases have been lower than those usually associated with reports of fatality with either
substance alone.
As in all cases of drug overdosage, respiration, pulse, and blood pressure should be monitored and supported
by general measures when necessary. Immediate gastric lavage should be performed. An adequate airway
should be maintained. Intravenous fluids may be administered.
Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of
the sedative effects of benzodiazepines and may be used in situations when an overdose with a
benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should
be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not
as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should
be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an
appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with
flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant
overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and
PRECAUTIONS should be consulted prior to use.
Experiments in animals have indicated that cardiopulmonary collapse can occur with massive intravenous
doses of triazolam. This could be reversed with positive mechanical respiration and the intravenous infusion
of norepinephrine bitartrate or metaraminol bitartrate. Hemodialysis and forced diuresis are probably of little
value. As with the management of intentional overdosage with any drug, the physician should bear in mind
that multiple agents may have been ingested by the patient.
The oral LD50 in mice is greater than 1,000 mg/kg and in rats is greater than 5,000 mg/kg.
DOSAGE AND ADMINISTRATION
It is important to individualize the dosage of HALCION Tablets for maximum beneficial effect and to help
avoid significant adverse effects.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17-892 S038 FDA approved labeling text 2.11.08
11
The recommended dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg may be found to be
sufficient for some patients (e.g., low body weight). A dose of 0.5 mg should be used only for exceptional
patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions
increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded.
In geriatric and/or debilitated patients the recommended dosage range is 0.125 mg to 0.25 mg. Therapy
should be initiated at 0.125 mg in these groups and the 0.25 mg dose should be used only for exceptional
patients who do not respond to a trial of the lower dose. A dose of 0.25 mg should not be exceeded in these
patients.
As with all medications, the lowest effective dose should be used.
HOW SUPPLIED
HALCION Tablets are available in the following strengths and package sizes:
0.125 mg (white, elliptical, imprinted HALCION 0.125):
Reverse numbered
Unit Dose (100)
NDC 0009-0010-32
10–10 Tablet Bottles
NDC 0009-0010-38
Bottles of 500
NDC 0009-0010-11
0.25 mg (powder blue, elliptical, scored, imprinted HALCION 0.25):
Reverse numbered
Unit Dose (100)
NDC 0009-0017-55
10–10 Tablet Bottles
NDC 0009-0017-59
Bottles of 500
NDC 0009-0017-02
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17-892 S038 FDA approved labeling text 2.11.08
12
MEDICATION GUIDE
HALCION Tablets/ C-IV
Read this Medication Guide before you start taking HALCION and each time you get a refill. There may be new
information. This Medication Guide does not take the place of talking to your doctor about your medical condition or
treatment. You and your doctor should talk about the SEDATIVE-HYPNOTIC when you start taking it and at regular
checkups.
What is the most important information I should
know about Halcion?
After taking a SEDATIVE-HYPNOTIC, you may get
up out of bed while not being fully awake and do
an activity that you do not know you are doing. The
next morning, you may not remember that you did
anything during the night. You have a higher chance
for doing these activities if you drink alcohol or take
other medicines that make you sleepy with a
SEDATIVE-HYPNOTIC. Reported activities include:
•
driving a car ("sleep-driving")
•
making and eating food
•
talking on the phone
•
having sex
•
sleep-walking
Important:
1. Take Halcion exactly as prescribed
•
Do not take more Halcion than prescribed.
•
Take Halcion right before you get in bed, not
sooner.
2. Do not take HALCION if you:
•
drink alcohol
•
take other medicines that can make you sleepy.
Talk to your doctor about all of your medicines.
Your doctor will tell you if you can take HALCION
with your other medicines
•
cannot get a full night’s sleep
•
are pregnant or considering becoming pregnant
3. Call your doctor right away if you find out that
you have done any of the above activities after
taking Halcion.
What are SEDATIVE-HYPNOTICS?
SEDATIVE-HYPNOTICs
are
sleep
medicines.
SEDATIVE-HYPNOTICS are used in adults for the
treatment of the symptom of trouble falling asleep due
to insomnia.
Halcion is not indicated for use in children.
Elderly patients are especially susceptible to dose
related adverse effects when taking Halcion.
Halcion is a federally controlled substance (C-IV)
because it can be abused or lead to dependence.
Keep Halcion in a safe place to prevent misuse and
abuse. Selling or giving away Halcion may harm
others, and is against the law. Tell your doctor if you
have ever abused or been dependent on alcohol,
prescription medicines or street drugs.
Who should not take Halcion?
Do not take Halcion if you are allergic to anything in it.
See the end of this Medication Guide for a complete
list of ingredients in HALCION.
SEDATIVE-HYPNOTICS may not be right for you.
Before starting SEDATIVE-HYPNOTICS, tell your
doctor about all of your health conditions,
including if you:
• have a history of depression, mental illness, or
suicidal thoughts
• have a history of drug or alcohol abuse or addiction
• have kidney or liver disease
• have a lung disease or breathing problems
• are pregnant, planning to become pregnant, or
breastfeeding
Tell your doctor about all of the medicines you take
including prescription and nonprescription medicines,
vitamins and herbal supplements. Medicines can
interact, sometimes causing side effects. Do not take
SEDATIVE-HYPNOTICS with other medicines that
can make you sleepy.
Know the medicines you take. Keep a list of your
medicines with you to show your doctor and
pharmacist each time you get a new medicine.
Halcion should not be taken with potent inhibitors of
CYP
3A
including
ketoconazole,
itraconazole,
nefazodone and possibly other azole-type antifungal
agents.
How should I take Halcion?
•
Take Halcion exactly as prescribed. Do not take
more Halcion than prescribed for you.
•
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17-892 S038 FDA approved labeling text 2.11.08
13
•
Take Halcion right before you get into bed. Or
you can take Halcion after you have been in bed
and have trouble falling asleep.
•
Do not take Halcion with or right after a meal.
•
Do not take Halcion unless you are able to get
a full night’s sleep before you must be active
again.
•
Call your healthcare provider if your insomnia
worsens or is not better within 7 to 10 days.
This may mean that there is another condition
causing your sleep problem.
•
If you take too much Halcion or overdose, call your
doctor or poison control center right away, or get
emergency treatment.
What are the possible side effects of SEDATIVE-
HYPNOTICS?
Serious side effects of SEDATIVE-HYPNOTICS
include:
•
getting out of bed while not being fully awake
and do an activity that you do not know you are
doing. (See “What is the most important
information I should know about SEDATIVE-
HYPNOTICS?)
•
abnormal thoughts and behavior. Symptoms
include more outgoing or aggressive behavior than
normal, confusion, agitation, hallucinations,
worsening of depression, and suicidal thoughts or
actions.
•
memory loss, including “traveler’s amnesia”
•
anxiety
•
severe allergic reactions. Symptoms include
swelling of the tongue or throat, trouble breathing,
and nausea and vomiting. Get emergency medical
help if you get these symptoms after taking
SEDATIVE-HYPNOTICS.
Call your doctor right away if you have any of the
above side effects or any other side effects that
worry you while using the SEDATIVE-HYPNOTIC.
Common side effects of HALCION include:
•
drowsiness
•
headache
•
dizziness
•
lightheadedness
•
“pins and needles” feelings on your skin
•
difficulty with coordination
•
You may still feel drowsy the next day after taking
HALCION. Do not drive or do other dangerous
activities (including operating machinery)) after
taking HALCION until you feel fully awake.
•
You may have withdrawal symptoms for 1 to 2
days when you stop taking the SEDATIVE-
HYPNOTIC suddenly. Withdrawal symptoms
include trouble sleeping, unpleasant feelings,
stomach and muscle cramps, vomiting, sweating,
shakiness, and seizures.
These are not all the side effects of SEDATIVE-
HYPNOTICS. Ask your doctor or pharmacist for more
information.
How should I store Halcion?
•
Store Halcion at room temperature between 68°
and 77° F (20º to 25ºC).
•
Protect from light.
•
Keep Halcion and all medicines out of the
reach of children.
•
Do not use Halcion after the expiration date on
the bottle.
General Information about SEDATIVE-HYPNOTICS
•
Medicines are sometimes prescribed for purposes
not mentioned in a Medication Guide.
•
Do not use the SEDATIVE-HYPNOTIC for a
condition for which it was not prescribed.
•
Do not give the SEDATIVE-HYPNOTIC to other
people, even if they have the same condition. It
may harm them and it is against the law.
This Medication Guide summarizes the most important
information about Halcion. If you would like more
information, talk with your doctor. You can ask your
doctor or pharmacist for information about Halcion that
was written for healthcare professionals.
If you would like more information, contact 1-800-879-
3477
What are the ingredients in HALCION?
Active Ingredient: Triazolam
Inactive Ingredients: 0.125 mg tablet: cellulose,
corn starch, docusate sodium, lactose, magnesium
stearate, silicon dioxide, sodium benzoate, 0.25 mg
tablet: cellulose, corn starch, docusate sodium,
FD&C Blue No. 2, lactose, magnesium stearate,
silicon dioxide, sodium benzoate.
___________________
Rx only
Manufactured and Distributed by: Pharmacia & Upjohn
Company
This Medication Guide has been approved by the U.S.
Food and Drug Administration. February, 2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17-892 S038 FDA approved labeling text 2.11.08
14
LAB-0259-5.0
Revised February 2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:23.755115
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017892s038lbl.pdf', 'application_number': 17892, 'submission_type': 'SUPPL ', 'submission_number': 38}
|
11,084
|
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:23.761139
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/017874s18s27lbl.pdf', 'application_number': 17874, 'submission_type': 'SUPPL ', 'submission_number': 27}
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NDA 17-911/S-068
Page 3
TABLETS
CLINORIL®
(SULINDAC)
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,
myocardial infarction, and stroke, which can be fatal. This risk may increase with
duration of use. Patients with cardiovascular disease or risk factors for cardiovascular
disease may be at greater risk (See WARNINGS).
• CLINORIL is contraindicated for the treatment of peri-operative pain in the setting of
coronary artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including
bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.
These events can occur at any time during use and without warning symptoms. Elderly
patients are at greater risk for serious gastrointestinal events (See WARNINGS).
DESCRIPTION
Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-
fluoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic
acid.
It
is
not
a
salicylate, pyrazolone or propionic acid derivative. Its empirical formula is C20H17FO3S, with a
molecular weight of 356.42. Sulindac, a yellow crystalline compound, is a weak organic acid
practically insoluble in water below pH 4.5, but very soluble as the sodium salt or in buffers of pH 6 or
higher.
CLINORIL* (Sulindac) is available in 150 and 200 mg tablets for oral administration. Each tablet
contains the following inactive ingredients: cellulose, magnesium stearate, starch.
Following absorption, sulindac undergoes two major biotransformations ⎯ reversible reduction to
the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Available evidence
indicates that the biological activity resides with the sulfide metabolite.
The structural formulas of sulindac and its metabolites are:
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1988, 2005 MERCK & CO., Inc.
All rights reserved
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-068
Page 4
CLINICAL PHARMACOLOGY
CLINORIL is a non-steroidal anti-inflammatory drug, also possessing analgesic and antipyretic
activities. Its mode of action, like that of other non-steroidal anti-inflammatory agents, is not known;
however, its therapeutic action is not due to pituitary-adrenal stimulation. Inhibition of prostaglandin
synthesis by the sulfide metabolite may be involved in the anti-inflammatory action of CLINORIL.
Sulindac is approximately 90% absorbed in man after oral administration. The peak plasma
concentrations of the biologically active sulfide metabolite are achieved in about two hours when
sulindac is administered in the fasting state, and in about three to four hours when sulindac is
administered with food. The mean half-life of sulindac is 7.8 hours while the mean half-life of the
sulfide metabolite is 16.4 hours. Sustained plasma levels of the sulfide metabolite are consistent with a
prolonged anti-inflammatory action which is the rationale for a twice per day dosage schedule.
Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the
sulfide metabolite in animals. Studies in man have also demonstrated that recirculation of the parent
drug, sulindac, and its sulfone metabolite, is more extensive than that of the active sulfide metabolite.
The active sulfide metabolite accounts for less than six percent of the total intestinal exposure to
sulindac and its metabolites.
The primary route of excretion in man is via the urine as both sulindac and its sulfone metabolite
(free and glucuronide conjugates). Approximately 50% of the administered dose is excreted in the
urine, with the conjugated sulfone metabolite accounting for the major portion. Less than 1% of the
administered dose of sulindac appears in the urine as the sulfide metabolite. Approximately 25% is
found in the feces, primarily as the sulfone and sulfide metabolites.
The bioavailability of sulindac, as assessed by urinary excretion, was not changed by concomitant
administration of an antacid containing magnesium hydroxide 200 mg and aluminum hydroxide
225 mg per 5 mL.
Because CLINORIL is excreted in the urine primarily as biologically inactive forms, it may
possibly affect renal function to a lesser extent than other non-steroidal anti-inflammatory drugs,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-068
Page 5
however, renal adverse experiences have been reported with CLINORIL (see ADVERSE
REACTIONS). In a study of patients with chronic glomerular disease treated with therapeutic doses
of CLINORIL, no effect was demonstrated on renal blood flow, glomerular filtration rate, or urinary
excretion of prostaglandin E2 and the primary metabolite of prostacyclin, 6-keto-PGF1α . However, in
other studies in healthy volunteers and patients with liver disease, CLINORIL was found to blunt the
renal responses to intravenous furosemide, i.e., the diuresis, natriuresis, increments in plasma renin
activity and urinary excretion of prostaglandins. These observations may represent a differentiation of
the effects of CLINORIL on renal functions based on differences in pathogenesis of the renal
prostaglandin dependence associated with differing dose-response relationships of different NSAIDs to
the various renal functions influenced by prostaglandins. These observations need further clarification
and in the interim, sulindac should be used with caution in patients whose renal function may be
impaired (see WARNINGS).
In healthy men, the average fecal blood loss, measured over a two-week period during
administration of 400 mg per day of CLINORIL, was similar to that for placebo, and was statistically
significantly less than that resulting from 4800 mg per day of aspirin.
In controlled clinical studies CLINORIL was evaluated in the following five conditions:
1. Osteoarthritis
In patients with osteoarthritis of the hip and knee, the anti-inflammatory and analgesic activity of
CLINORIL was demonstrated by clinical measurements that included: assessments by both patient and
investigator of overall response; decrease in disease activity as assessed by both patient and
investigator; improvement in ARA Functional Class; relief of night pain; improvement in overall
evaluation of pain, including pain on weight bearing and pain on active and passive motion;
improvement in joint mobility, range of motion, and functional activities; decreased swelling and
tenderness; and decreased duration of stiffness following prolonged inactivity.
In clinical studies in which dosages were adjusted according to patient needs, CLINORIL 200 to
400 mg daily was shown to be comparable in effectiveness to aspirin 2400 to 4800 mg daily.
CLINORIL was generally well tolerated, and patients on it had a lower overall incidence of total
adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin (See
ADVERSE REACTIONS).
2. Rheumatoid arthritis
In patients with rheumatoid arthritis, the anti-inflammatory and analgesic activity of CLINORIL
was demonstrated by clinical measurements that included: assessments by both patient and investigator
of overall response; decrease in disease activity as assessed by both patient and investigator; reduction
in overall joint pain; reduction in duration and severity of morning stiffness; reduction in day and night
pain; decrease in time required to walk 50 feet; decrease in general pain as measured on a visual analog
scale; improvement in the Ritchie articular index; decrease in proximal interphalangeal joint size;
improvement in ARA Functional Class; increase in grip strength; reduction in painful joint count and
score; reduction in swollen joint count and score; and increased flexion and extension of the wrist.
In clinical studies in which dosages were adjusted according to patient needs, CLINORIL 300 to
400 mg daily was shown to be comparable in effectiveness to aspirin 3600 to 4800 mg daily.
CLINORIL was generally well tolerated, and patients on it had a lower overall incidence of total
adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin (See
ADVERSE REACTIONS).
In patients with rheumatoid arthritis, CLINORIL may be used in combination with gold salts at
usual dosage levels. In clinical studies, CLINORIL added to the regimen of gold salts usually resulted
in additional symptomatic relief but did not alter the course of the underlying disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-068
Page 6
3. Ankylosing spondylitis
In patients with ankylosing spondylitis, the anti-inflammatory and analgesic activity of CLINORIL
was demonstrated by clinical measurements that included: assessments by both patient and investigator
of overall response; decrease in disease activity as assessed by both patient and investigator;
improvement in ARA Functional Class; improvement in patient and investigator evaluation of spinal
pain, tenderness and/or spasm; reduction in the duration of morning stiffness; increase in the time to
onset of fatigue; relief of night pain; increase in chest expansion; and increase in spinal mobility
evaluated by fingers-to-floor distance, occiput to wall distance, the Schober Test, and the Wright
Modification of the Schober Test. In a clinical study in which dosages were adjusted according to
patient need, CLINORIL 200 to 400 mg daily was as effective as indomethacin 75 to 150 mg daily. In
a second study, CLINORIL 300 to 400 mg daily was comparable in effectiveness to phenylbutazone
400 to 600 mg daily. CLINORIL was better tolerated than phenylbutazone. (See ADVERSE
REACTIONS.)
4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
In patients with acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), the
anti-inflammatory and analgesic activity of CLINORIL was demonstrated by clinical measurements
that included: assessments by both patient and investigator of overall response; relief of night pain,
spontaneous pain, and pain on active motion; decrease in local tenderness; and improvement in range
of motion measured by abduction, and internal and external rotation. In clinical studies in acute painful
shoulder, CLINORIL 300 to 400 mg daily and oxyphenbutazone 400 to 600 mg daily were shown to
be equally effective and well tolerated.
5. Acute gouty arthritis
In patients with acute gouty arthritis, the anti-inflammatory and analgesic activity of CLINORIL
was demonstrated by clinical measurements that included: assessments by both the patient and
investigator of overall response; relief of weight-bearing pain; relief of pain at rest and on active and
passive motion; decrease in tenderness; reduction in warmth and swelling; increase in range of motion;
and improvement in ability to function. In clinical studies, CLINORIL at 400 mg daily and
phenylbutazone at 600 mg daily were shown to be equally effective. In these short-term studies in
which reduction of dosage was permitted according to response, both drugs were equally well
tolerated.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of CLINORIL and other treatment options before
deciding to use CLINORIL. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
CLINORIL is indicated for acute or long-term use in the relief of signs and symptoms of the
following:
1. Osteoarthritis
2. Rheumatoid arthritis**
3. Ankylosing spondylitis
4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
**The safety and effectiveness of CLINORIL have not been established in rheumatoid arthritis patients who are designated in the American Rheumatism
Association classification as Functional Class IV (incapacitated, largely or wholly bedridden, or confined to wheelchair; little or no self-care).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-068
Page 7
5. Acute gouty arthritis
CONTRAINDICATIONS
CLINORIL is contraindicated in patients with known hypersensitivity to sulindac or the excipients
(see DESCRIPTION).
CLINORIL should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid
reactions
to
NSAIDs
have
been
reported
in
such
patients
(see
WARNINGS,
Anaphylactic/Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma).
CLINORIL is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration
have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction,
and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a
similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the
first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and
stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including CLINORIL, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including CLINORIL, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout
the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. CLINORIL should
be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including CLINORIL, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-068
Page 8
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of
patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk for GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the
lowest effective dose should be used for the shortest possible duration. Patients and physicians should
remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and
promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This
should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high
risk patients, alternate therapies that do not involve NSAIDs should be considered.
Hepatic Effects
In addition to hypersensitivity reactions involving the liver, in some patients the findings are
consistent with those of cholestatic hepatitis (see WARNINGS, Hypersensitivity). . As with other non-
steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests without any other
signs and symptoms may occur in up to 15% of patients taking NSAIDs including CLINORIL. These
laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with
continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction.
Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in
controlled clinical trials in less than 1% of patients. Notable elevations of ALT or AST (approximately
three or more times the upper limit of normal) have been reported in approximately 1% of patients in
clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and
fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have
been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver
test has occurred, should be evaluated for evidence of the development of a more severe hepatic
reaction while on therapy with CLINORIL. Although such reactions as described above are rare, if
abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), CLINORIL should be
discontinued.
In clinical trials with CLINORIL, the use of doses of 600 mg/day has been associated with an
increased incidence of mild liver test abnormalities (see DOSAGE AND ADMINISTRATION for
maximum dosage recommendation).
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-068
Page 9
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE inhibitors, patients who are volume depleted, and the elderly. Discontinuation of NSAID
therapy is usually followed by recovery to the pretreatment state.
Caution should be used when initiating the treatment with CLINORIL in patients with considerable
dehydration. It is advisable to rehydrate patients first and then start therapy with CLINORIL. Caution
is also recommended in patients with preexisting kidney disease.
Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in
association with other calculus components. CLINORIL should be used with caution in patients with a
history of renal lithiasis, and they should be kept well hydrated while receiving CLINORIL.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of CLINORIL in
patients with advanced renal disease. Therefore, treatment with CLINORIL is not recommended in
these patients with advanced renal disease. If CLINORIL therapy must be initiated, close monitoring
of the patient’s renal function is advisable.
Since CLINORIL is eliminated primarily by the kidneys, patients with significantly impaired renal
function should be closely monitored; a lower daily dosage should be anticipated to avoid excessive
drug accumulation.
Anaphylactic/Anaphylactoid Reactions
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known
prior exposure to CLINORIL. CLINORIL should not be given to patients with the aspirin triad. This
symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal
polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactic/anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including CLINORIL, can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be
fatal. These serious events may occur without warning. Patients should be informed about the signs
and symptoms of serious skin manifestations and use of the drug should be discontinued at the first
appearance of skin rash or any other sign of hypersensitivity.
Hypersensitivity
Rarely, fever and other evidence of hypersensitivity (see ADVERSE REACTIONS) including
abnormalities in one or more liver function tests and severe skin reactions have occurred during
therapy with CLINORIL. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with
or without fever, may occur usually within the first one to three months of therapy. Determinations of
liver function should be considered whenever a patient on therapy with CLINORIL develops
unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained
fever or other evidence of hypersensitivity occurs, therapy with CLINORIL should be discontinued.
The elevated temperature and abnormalities in liver function caused by CLINORIL characteristically
have reverted to normal after discontinuation of therapy. Administration of CLINORIL should not be
reinstituted in such patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-068
Page 10
Pregnancy
In late pregnancy, as with other NSAIDs, CLINORIL should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
CLINORIL cannot be expected to substitute for corticosteroids or to treate corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on
prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to
discontinue corticosteroids.
The pharmacological activity of CLINORIL in reducing fever and inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including CLINORIL. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including CLINORIL, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some
patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and
reversible. Patients receiving CLINORIL who may be adversely affected by alterations in platelet
function, such as those with coagulation disorders or patients receiving anticoagulants, should be
carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs
has been reported in such aspirin-sensitive patients, CLINORIL should not be administered to patients
with this form of aspirin sensitivity and should be used with caution in patients with preexisting
asthma.
Renal Calculi
Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in
association with other calculus components. CLINORIL should be used with caution in patients with a
history of renal lithiasis, and they should be kept well hydrated while receiving CLINORIL.
Pancreatitis
Pancreatitis has been reported in patients receiving CLINORIL (see ADVERSE REACTIONS).
Should pancreatitis be suspected, the drug should be discontinued and not restarted, supportive medical
therapy instituted, and the patient monitored closely with appropriate laboratory studies (e.g., serum
and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase,
etc.). A search for other causes of pancreatitis as well as those conditions which mimic pancreatitis
should be conducted.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-068
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Ocular Effects
Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is
recommended that patients who develop eye complaints during treatment with CLINORIL have
ophthalmologic studies.
Hepatic Insufficiency
In patients with poor liver function, delayed, elevated and prolonged circulating levels of the sulfide
and sulfone metabolites may occur. Such patients should be monitored closely; a reduction of daily
dosage may be required.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
1. CLINORIL, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which
may result in hospitalization and even death. Although serious CV events can occur without
warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any
indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see
WARNINGS, CARDIOVASCULAR EFFECTS).
2. CLINORIL, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such
as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI
tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for
the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when
observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and
hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
3. CLINORIL, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis,
SJS, and TEN, which may result in hospitalizations and even death. Although serious skin
reactions may occur without warning, patients should be alert for the signs and symptoms of skin
rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for
medical advice when observing any indicative signs or symptoms. Patients should be advised to
stop the drug immediately if they develop any type of rash and contact their physicians as soon as
possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty
breathing, swelling of the face or throat). If these occur, patients should be instructed to seek
immediate emergency help (see WARNINGS).
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NDA 17-911/S-068
Page 12
7. In late pregnancy, as with other NSAIDs, CLINORIL should be avoided because it may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, CLINORIL should be discontinued.
Drug Interactions
ACE-Inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and
angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs
concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised
renal function, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II
antagonist may result in further deterioration of renal function, including possible acute renal failure,
which is usually reversible.
Acetaminophen
Acetaminophen had no effect on the plasma levels of sulindac or its sulfide metabolite.
Aspirin
When CLINORIL is administered with aspirin, its protein binding is reduced, although the
clearance of free CLINORIL is not altered. The clinical significance of this interaction is not known;
however, as with other NSAIDs, concomitant administration of sulindac and aspirin is not generally
recommended because of the potential of increased adverse effects
.
The concomitant administration of aspirin with sulindac significantly depressed the plasma levels of
the active sulfide metabolite. A double-blind study compared the safety and efficacy of CLINORIL
300 or 400 mg daily given alone or with aspirin 2.4 g/day for the treatment of osteoarthritis. The
addition of aspirin did not alter the types of clinical or laboratory adverse experiences for CLINORIL;
however, the combination showed an increase in the incidence of gastrointestinal adverse experiences.
Since the addition of aspirin did not have a favorable effect on the therapeutic response to CLINORIL,
the combination is not recommended.
Cyclosporine
Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been
associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of
renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal
function should be carefully monitored.
Diflunisal
The concomitant administration of CLINORIL and diflunisal in normal volunteers resulted in
lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.
Diuretics
Clinical studies, as well as post marketing observations, have shown that CLINORIL can reduce the
natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to
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NDA 17-911/S-068
Page 13
inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient
should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to
assure diuretic efficacy.
DMSO
DMSO should not be used with sulindac. Concomitant administration has been reported to reduce
the plasma levels of the active sulfide metabolite and potentially reduce efficacy. In addition, this
combination has been reported to cause peripheral neuropathy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney
slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used
when NSAIDs are administered concomitantly with methotrexate.
NSAIDs
The concomitant use of CLINORIL with other NSAIDs is not recommended due to the increased
possibility of gastrointestinal toxicity, with little or no increase in efficacy.
Oral anticoagulants
Although sulindac and its sulfide metabolite are highly bound to protein, studies in which
CLINORIL was given at a dose of 400 mg daily have shown no clinically significant interaction with
oral anticoagulants. However, patients should be monitored carefully until it is certain that no change
in their anticoagulant dosage is required. Special attention should be paid to patients taking higher
doses than those recommended and to patients with renal impairment or other metabolic defects that
might increase sulindac blood levels. The effects of warfarin and NSAIDs on GI bleeding are
synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users
of either drug alone.
Oral hypoglycemic agents
Although sulindac and its sulfide metabolite are highly bound to protein, studies in which
CLINORIL was given at a dose of 400 mg daily, have shown no clinically significant interaction with
oral hypoglycemic agents. However, patients should be monitored carefully until it is certain that no
change in their hypoglycemic dosage is required. Special attention should be paid to patients taking
higher doses than those recommended and to patients with renal impairment or other metabolic defects
that might increase sulindac blood levels.
Probenecid
Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels,
while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest
reduction in the uricosuric action of probenecid, which probably is not significant under most
circumstances.
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NDA 17-911/S-068
Page 14
Propoxyphene hydrochloride
Propoxyphene hydrochloride had no effect on the plasma levels of sulindac or its sulfide metabolite.
Pregnancy
Teratogenic Effects. Pregnancy Category C.
CLINORIL is not recommended for use in pregnant women, since safety for use has not been
established. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of
developmental abnormalities. However, animal reproduction studies are not always predictive of
human response. There are no adequate and well-controlled studies in pregnant women. Clinoril
should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
The known effects of drugs of this class on the human fetus during the third trimester of pregnancy
include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary
hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical
management; myocardial degenerative changes, platelet dysfunction with resultant bleeding,
intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in
prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and
increased risk of necrotizing enterocolitis.
In reproduction studies in the rat, a decrease in average fetal weight and an increase in numbers of
dead pups were observed on the first day of the postpartum period at dosage levels of 20 and 40
mg/kg/day (2½ and 5 times the usual maximum daily dose in humans), although there was no adverse
effect on the survival and growth during the remainder of the postpartum period. CLINORIL prolongs
the duration of gestation in rats, as do other compounds of this class. Visceral and skeletal
malformations observed in low incidence among rabbits in some teratology studies did not occur at the
same dosage levels in repeat studies, nor at a higher dosage level in the same species.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an
increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects
of CLINORIL on labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk; however, it is secreted in the milk of
lactating rats. Because many drugs are excreted in human-milk and because of the potential for serious
adverse reactions in nursing infants from CLINORIL, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the
mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since
advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate
ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events
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NDA 17-911/S-068
Page 15
are in this population (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and
Perforation).
This DRUGCLINORIL is known to be substantially excreted by the kidney and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection and it may be
useful to monitor renal function (see WARNINGS, Renal Effects).
ADVERSE REACTIONS
The following adverse reactions were reported in clinical trials or have been reported since the drug
was marketed. The probability exists of a causal relationship between CLINORIL and these adverse
reactions. The adverse reactions which have been observed in clinical trials encompass observations in
1,865 patients, including 232 observed for at least 48 weeks.
Incidence Greater Than 1%
Gastrointestinal
The most frequent types of adverse reactions occurring with CLINORIL are gastrointestinal; these
include gastrointestinal pain (10%), dyspepsia***, nausea*** with or without vomiting, diarrhea***,
constipation***, flatulence, anorexia and gastrointestinal cramps.
Dermatologic
Rash***, pruritus.
Central Nervous System
Dizziness***, headache***, nervousness.
Special Senses
Tinnitus.
Miscellaneous
Edema (see WARNINGS).
Incidence Less Than 1 in 100
Gastrointestinal
Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI
perforation and intestinal strictures (diaphragms) have been reported rarely.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.
There have been rare reports of sulindac metabolites in common bile duct "sludge" and in biliary
calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy.
Pancreatitis (see PRECAUTIONS).
Ageusia; glossitis.
Dermatologic
Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.
Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative
dermatitis have been reported.
Cardiovascular
Congestive heart failure, especially in patients with marginal cardiac function; palpitation;
hypertension.
Hematologic
Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow
depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on
oral anticoagulants (see PRECAUTIONS).
*** Incidence between 3% and 9%. Those reactions occurring in 1% to 3% of patients are not marked with an asterisk.
This label may not be the latest approved by FDA.
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NDA 17-911/S-068
Page 16
Genitourinary
Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal
impairment, including renal failure; interstitial nephritis; nephrotic syndrome.
Renal calculi containing sulindac metabolites have been observed rarely.
Metabolic
Hyperkalemia.
Musculoskeletal
Muscle weakness.
Psychiatric
Depression; psychic disturbances including acute psychosis.
Nervous System
Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis.
Special Senses
Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste.
Respiratory
Epistaxis.
Hypersensitivity Reactions
Anaphylaxis; angioneurotic edema; bronchial spasm; dyspnea.
Hypersensitivity vasculitis.
A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may
include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other
dermatologic reactions ⎯ see above), conjunctivitis, involvement of major organs (changes in liver
function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion,
leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal
impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis,
myalgia, fatigue, malaise, hypotension, chest pain, tachycardia).
Causal Relationship Unknown
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A
β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory
agents, sometimes with fatal outcome (see also PRECAUTIONS, General).
Other reactions have been reported in clinical trials or since the drug was marketed, but occurred
under circumstances where a causal relationship could not be established. However, in these rarely
reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as
alerting information to physicians.
Cardiovascular
Arrhythmia.
Metabolic
Hyperglycemia.
Nervous System
Neuritis.
Special Senses
Disturbances of the retina and its vasculature.
Miscellaneous
Gynecomastia.
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NDA 17-911/S-068
Page 17
MANAGEMENT OF OVERDOSAGE
Cases of overdosage have been reported and rarely, deaths have occurred. The following signs and
symptoms may be observed following overdosage: stupor, coma, diminished urine output and
hypotension.
In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric
lavage, and the patient carefully observed and given symptomatic and supportive treatment.
Animal studies show that absorption is decreased by the prompt administration of activated charcoal
and excretion is enhanced by alkalinization of the urine.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of CLINORIL and other treatment options before
deciding to use CLINORIL. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with CLINORIL, the dose and frequency should be
adjusted to suit an individual patient’s needs.
CLINORIL should be administered orally twice a day with food. The maximum dosage is 400 mg per
day. Dosages above 400 mg per day are not recommended.
In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended starting dosage
is 150 mg twice a day. The dosage may be lowered or raised depending on the response.
A prompt response (within one week) can be expected in about one-half of patients with
osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis. Others may require longer to respond.
In acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis) and acute gouty
arthritis, the recommended dosage is 200 mg twice a day. After a satisfactory response has been
achieved, the dosage may be reduced according to the response. In acute painful shoulder, therapy for
7-14 days is usually adequate. In acute gouty arthritis, therapy for 7 days is usually adequate.
HOW SUPPLIED
No. 3360 ⎯ Tablets CLINORIL 150 mg are bright yellow, hexagon-shaped, compressed tablets,
coded MSD 941 on one side and CLINORIL on the other. They are supplied as follows:
NDC 0006-0941-68 in bottles of 100
(6505-01-071-5559, 150 mg 100's).
No. 3353 ⎯ Tablets CLINORIL 200 mg are bright yellow, hexagon-shaped, scored, compressed
tablets, coded MSD 942 on one side and CLINORIL on the other. They are supplied as follows:
NDC 0006-0942-68 in bottles of 100
(6505-01-072-3426, 200 mg 100's).
Distributed by:
Manufactured by:
MERCK SHARP & DOHME Pty., Ltd.
South Granville, NSW, Australia 2142.
Issued July 2005
Printed in USA
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NDA 17-911/S-068
Page 18
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
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Page 19
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and sticky
like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017911s068lbl.pdf', 'application_number': 17911, 'submission_type': 'SUPPL ', 'submission_number': 68}
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NDA 17-911/S-070
Page 3
TABLETS
CLINORIL®
(SULINDAC)
Cardiovascular Risk
•
NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients
with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
(See WARNINGS.)
•
CLINORIL is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
•
NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can
occur at any time during use and without warning symptoms. Elderly patients are at greater risk
for serious gastrointestinal events. (See WARNINGS.)
DESCRIPTION
Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-fluoro-2-
methyl-1-[[p-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid. It is not a salicylate, pyrazolone or
propionic acid derivative. Its empirical formula is C20H17FO3S, with a molecular weight of 356.42. Sulindac, a
yellow crystalline compound, is a weak organic acid practically insoluble in water below pH 4.5, but very soluble
as the sodium salt or in buffers of pH 6 or higher.
CLINORIL* (Sulindac) is available in 150 and 200 mg tablets for oral administration. Each tablet contains the
following inactive ingredients: cellulose, magnesium stearate, starch.
Following absorption, sulindac undergoes two major biotransformations ⎯ reversible reduction to the sulfide
metabolite, and irreversible oxidation to the sulfone metabolite. Available evidence indicates that the biological
activity resides with the sulfide metabolite.
The structural formulas of sulindac and its metabolites are:
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1988, 2005 MERCK & CO., Inc.
All rights reserved
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-070
Page 4
CLINICAL PHARMACOLOGY
Pharmacodynamics
CLINORIL is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and
antipyretic activities in animal models. The mechanism of action, like that of other NSAIDs, is not completely
understood but may be related to prostaglandin synthetase inhibition.
Pharmacokinetics
Absorption
The extent of sulindac absorption from CLINORIL Tablets is similar as compared to sulindac solution.
There is no information regarding food effect on sulindac absorption. Antacids containing magnesium
hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL have been shown not to significantly decrease the
extent of sulindac absorption.
TABLE 1
PHARMACOKINE
TIC PARAMETERS
NORMAL
ELDERLY
Tmax
Age 19-41 (n=24)
(200 mg tablet)
3.38 ± 2.30 S
4.88 ± 2.57 SP
4.96 ± 2.36 SF
(150 mg tablet)
3.90 ± 2.30 S
5.85 ±4.49 SP
Age 65-87 (n=12) 400 mg qd)
2.54 ± 1.52 S
5.75 ± 2.81 SF
6.83 ± 4.19 SP
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NDA 17-911/S-070
Page 5
6.15 ± 3.07 SF
Renal Clearance
(200 mg tablet)
68.12 ± 27.56 mL/min S
36.58 ± 12.61 mL/min SP
(150 mg tablet)
74.39 ± 34.15 mL/min S
41.75 ± 13.72 mL/min SP
Mean effective Half life
(h)
7.8 S
16.4 SF
S = Sulindac
SF = Sulindac Sulfide
SP = Sulindac Sulfone
Distribution
Sulindac, and its sulfone and sulfide metabolites, are 93.1, 95.4, and 97.9% bound to plasma proteins,
predominantly to albumin. Plasma protein binding measured over a concentration range (0.5-2.0 µg/mL) was
constant. Following an oral, radiolabeled dose of sulindac in rats, concentrations of radiolabel in red blood cells
were about 10% of those in plasma. Sulindac penetrates the blood-brain and placental barriers. Concentrations
in brain did not exceed 4% of those in plasma. Plasma concentrations in the placenta and in the fetus were less
than 25% and 5% respectively, of systemic plasma concentrations. Sulindac is excreted in rat milk;
concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human
milk.
Metabolism
Sulindac undergoes two major biotransformations of its sulfoxide moiety: oxidation to the inactive sulfone
and reduction to the pharmacologically active sulfide. The latter is readily reversible in animals and in man.
These metabolites are present as unchanged compounds in plasma and principally as glucuronide conjugates
in human urine and bile. A dihydroxydihydro analog has also been identified as a minor metabolite in human
urine.
With the twice-a-day dosage regimen, plasma concentrations of sulindac and its two metabolites
accumulate: mean concentration over a dosage interval at steady state relative to the first dose averages 1.5
and 2.5 times higher, respectively, for sulindac and its active sulfide metabolite.
Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the sulfide
metabolite in animals. Studies in man have also demonstrated that recirculation of the parent drug sulindac and
its sulfone metabolite is more extensive than that of the active sulfide metabolite. The active sulfide metabolite
accounts for less than six percent of the total intestinal exposure to sulindac and its metabolites.
Biochemical as well as pharmacological evidence indicates that the activity of sulindac resides in its sulfide
metabolite. An in-vitro assay for inhibition of cyclooxygenase activity exhibited an EC50 of 0.02 µM for sulindac
sulfide. In-vivo models of inflammation indicate that activity is more highly correlated with concentrations of the
metabolite than with parent drug concentrations.
Elimination
Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated sulfone
metabolite accounting for the major portion. Less than 1% of the administered dose of sulindac appears in the
urine as the sulfide metabolite. Approximately 25% is found in the feces, primarily as the sulfone and sulfide
metabolites.
The mean effective half-life (T1/2) is 7.8 and 16.4 hours, respectively, for sulindac and its active sulfide
metabolite.
Because CLINORIL is excreted in the urine primarily as biologically inactive forms, it may possibly affect
renal function to a lesser extent than other non-steroidal anti-inflammatory drugs; however, renal adverse
experiences have been reported with CLINORIL (see ADVERSE REACTIONS).
In a study of patients with chronic glomerular disease treated with therapeutic doses of CLINORIL, no effect
was demonstrated on renal blood flow, glomerular filtration rate, or urinary excretion of prostaglandin E2 and the
primary metabolite of prostacyclin, 6-keto-PGF1α. However, in other studies in healthy volunteers and patients
with liver disease, CLINORIL was found to blunt the renal responses to intravenous furosemide, i.e., the
diuresis, natriuresis, increments in plasma renin activity and urinary excretion of prostaglandins. These
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NDA 17-911/S-070
Page 6
observations may represent a differentiation of the effects of CLINORIL on renal functions based on differences
in pathogenesis of the renal prostaglandin dependence associated with differing dose-response relationships of
different NSAIDs to the various renal functions influenced by prostaglandins (see PRECAUTIONS).
In healthy men, the average fecal blood loss, measured over a two-week period during administration of
400 mg per day of CLINORIL, was similar to that for placebo, and was statistically significantly less than that
resulting from 4800 mg per day of aspirin.
Special Populations
Pediatric
The pharmacokinetics of sulindac have not been investigated in pediatric patients.
Race
Pharmacokinetic differences due to race have not been identified.
Hepatic Insufficiency
Patients with acute and chronic hepatic disease may require reduced doses of CLINORIL compared to
patients with normal hepatic function since hepatic metabolism is an important elimination pathway.
Following a single dose, plasma concentrations of the active sulfide metabolite have been reported to be
higher in patients with alcoholic liver disease compared to healthy normal subjects.
Renal Insufficiency
Sulindac pharmacokinetics have been investigated in patients with renal insufficiency. The disposition of
sulindac was studied in end-stage renal disease patients requiring hemodialysis. Plasma concentrations of
sulindac and its sulfone metabolite were comparable to those of normal healthy volunteers whereas
concentrations of the active sulfide metabolite were significantly reduced. Plasma protein binding was reduced
and the AUC of the unbound sulfide metabolite was about half that in healthy subjects.
Sulindac and its metabolites are not significantly removed from the blood in patients undergoing
hemodialysis.
Since CLINORIL is eliminated primarily by the kidneys, patients with significantly impaired renal function
should be closely monitored.
A lower daily dosage should be anticipated to avoid excessive drug accumulation.
In controlled clinical studies CLINORIL was evaluated in the following five conditions:
1. Osteoarthritis
In patients with osteoarthritis of the hip and knee, the anti-inflammatory and analgesic activity of CLINORIL
was demonstrated by clinical measurements that included: assessments by both patient and investigator of
overall response; decrease in disease activity as assessed by both patient and investigator; improvement in
ARA Functional Class; relief of night pain; improvement in overall evaluation of pain, including pain on weight
bearing and pain on active and passive motion; improvement in joint mobility, range of motion, and functional
activities; decreased swelling and tenderness; and decreased duration of stiffness following prolonged inactivity.
In clinical studies in which dosages were adjusted according to patient needs, CLINORIL 200 to 400 mg daily
was shown to be comparable in effectiveness to aspirin 2400 to 4800 mg daily. CLINORIL was generally well
tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal
reactions, and of tinnitus than did patients on aspirin. (See ADVERSE REACTIONS.)
2. Rheumatoid arthritis
In patients with rheumatoid arthritis, the anti-inflammatory and analgesic activity of CLINORIL was
demonstrated by clinical measurements that included: assessments by both patient and investigator of overall
response; decrease in disease activity as assessed by both patient and investigator; reduction in overall joint
pain; reduction in duration and severity of morning stiffness; reduction in day and night pain; decrease in time
required to walk 50 feet; decrease in general pain as measured on a visual analog scale; improvement in the
Ritchie articular index; decrease in proximal interphalangeal joint size; improvement in ARA Functional Class;
increase in grip strength; reduction in painful joint count and score; reduction in swollen joint count and score;
and increased flexion and extension of the wrist.
In clinical studies in which dosages were adjusted according to patient needs, CLINORIL 300 to 400 mg daily
was shown to be comparable in effectiveness to aspirin 3600 to 4800 mg daily. CLINORIL was generally well
tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal
reactions, and of tinnitus than did patients on aspirin. (See ADVERSE REACTIONS.)
In patients with rheumatoid arthritis, CLINORIL may be used in combination with gold salts at usual dosage
levels. In clinical studies, CLINORIL added to the regimen of gold salts usually resulted in additional
symptomatic relief but did not alter the course of the underlying disease.
3. Ankylosing spondylitis
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NDA 17-911/S-070
Page 7
In patients with ankylosing spondylitis, the anti-inflammatory and analgesic activity of CLINORIL was
demonstrated by clinical measurements that included: assessments by both patient and investigator of overall
response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA
Functional Class; improvement in patient and investigator evaluation of spinal pain, tenderness and/or spasm;
reduction in the duration of morning stiffness; increase in the time to onset of fatigue; relief of night pain;
increase in chest expansion; and increase in spinal mobility evaluated by fingers-to-floor distance, occiput to
wall distance, the Schober Test, and the Wright Modification of the Schober Test. In a clinical study in which
dosages were adjusted according to patient need, CLINORIL 200 to 400 mg daily was as effective as
indomethacin 75 to 150 mg daily. In a second study, CLINORIL 300 to 400 mg daily was comparable in
effectiveness to phenylbutazone 400 to 600 mg daily. CLINORIL was better tolerated than phenylbutazone.
(See ADVERSE REACTIONS.)
4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
In patients with acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), the anti-
inflammatory and analgesic activity of CLINORIL was demonstrated by clinical measurements that included:
assessments by both patient and investigator of overall response; relief of night pain, spontaneous pain, and
pain on active motion; decrease in local tenderness; and improvement in range of motion measured by
abduction, and internal and external rotation. In clinical studies in acute painful shoulder, CLINORIL 300 to
400 mg daily and oxyphenbutazone 400 to 600 mg daily were shown to be equally effective and well tolerated.
5. Acute gouty arthritis
In patients with acute gouty arthritis, the anti-inflammatory and analgesic activity of CLINORIL was
demonstrated by clinical measurements that included: assessments by both the patient and investigator of
overall response; relief of weight-bearing pain; relief of pain at rest and on active and passive motion; decrease
in tenderness; reduction in warmth and swelling; increase in range of motion; and improvement in ability to
function. In clinical studies, CLINORIL at 400 mg daily and phenylbutazone at 600 mg daily were shown to be
equally effective. In these short-term studies in which reduction of dosage was permitted according to response,
both drugs were equally well tolerated.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of CLINORIL and other treatment options before deciding
to use CLINORIL. Use the lowest effective dose for the shortest duration consistent with individual patient
treatment goals (see WARNINGS).
CLINORIL is indicated for acute or long-term use in the relief of signs and symptoms of the following:
1. Osteoarthritis
2. Rheumatoid arthritis**
3. Ankylosing spondylitis
4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
5. Acute gouty arthritis
CONTRAINDICATIONS
CLINORIL is contraindicated in patients with known hypersensitivity to sulindac or the excipients (see
DESCRIPTION).
CLINORIL should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions
after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have
been reported in such patients (see WARNINGS – Anaphylactic/Anaphylactoid Reactions, and
PRECAUTIONS – Preexisting Asthma).
CLINORIL is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass
graft (CABG) surgery (see WARNINGS).
**The safety and effectiveness of CLINORIL have not been established in rheumatoid arthritis patients who are designated in the American Rheumatism
Association classification as Functional Class IV (incapacitated, largely or wholly bedridden, or confined to wheelchair; little or no self-care).
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NDA 17-911/S-070
Page 8
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown
an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can
be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV
disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV
event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration
possible. Physicians and patients should remain alert for the development of such events, even in the absence
of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events
and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV
thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the
risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14
days following CABG surgery found an increased incidence of myocardial infarction and stroke (see
CONTRAINDICATIONS).
Hypertension
NSAIDs, including CLINORIL, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides
or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including
CLINORIL, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored
closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. CLINORIL should be used
with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including CLINORIL, can cause serious gastrointestinal (GI) adverse events including inflammation,
bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These
serious adverse events can occur at any time, with or without warning symptoms, in patients treated with
NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy is
symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of
patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with
longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course
of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding
who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with
neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs
include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking,
use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in
elderly or debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective
dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs
and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation
and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until
a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs
should be considered.
Hepatic Effects
In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with
those of cholestatic hepatitis (see WARNINGS, Hypersensitivity). As with other non-steroidal anti-inflammatory
drugs, borderline elevations of one or more liver tests without any other signs and symptoms may occur in up to
15% of patients taking NSAIDs including CLINORIL. These laboratory abnormalities may progress, may remain
essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most
sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or
SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. Notable elevations of ALT or AST
(approximately three or more times the upper limit of normal) have been reported in approximately 1% of
patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and
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NDA 17-911/S-070
Page 9
fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been
reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has
occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on
therapy with CLINORIL. Although such reactions as described above are rare, if abnormal liver tests persist or
worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur
(e.g., eosinophilia, rash, etc.), CLINORIL should be discontinued.
In clinical trials with CLINORIL, the use of doses of 600 mg/day has been associated with an increased
incidence of mild liver test abnormalities (see DOSAGE AND ADMINISTRATION for maximum dosage
recommendation).
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal
toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may
cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal
function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-
depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment
state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of CLINORIL in patients with
advanced renal disease. Therefore, treatment with CLINORIL is not recommended in these patients with
advanced renal disease. If CLINORIL therapy must be initiated, close monitoring of the patient’s renal function is
advisable.
Anaphylactic/Anaphylactoid Reactions
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior
exposure to CLINORIL. CLINORIL should not be given to patients with the aspirin triad. This symptom complex
typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe,
potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and
PRECAUTIONS – Preexisting Asthma). Emergency help should be sought in cases where an
anaphylactic/anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including CLINORIL, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious
events may occur without warning. Patients should be informed about the signs and symptoms of serious skin
manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign
of hypersensitivity.
Hypersensitivity
Rarely, fever and other evidence of hypersensitivity (see ADVERSE REACTIONS) including abnormalities in
one or more liver function tests and severe skin reactions have occurred during therapy with CLINORIL.
Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without fever, may occur usually
within the first one to three months of therapy. Determinations of liver function should be considered whenever a
patient on therapy with CLINORIL develops unexplained fever, rash or other dermatologic reactions or
constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with
CLINORIL should be discontinued. The elevated temperature and abnormalities in liver function caused by
CLINORIL characteristically have reverted to normal after discontinuation of therapy. Administration of
CLINORIL should not be reinstituted in such patients.
Pregnancy
In late pregnancy, as with other NSAIDs, CLINORIL should be avoided because it may cause premature
closure of the ductus arteriosus.
PRECAUTIONS
General
CLINORIL cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt
discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid
therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of CLINORIL in reducing fever and inflammation may diminish the utility of
these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
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NDA 17-911/S-070
Page 10
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including CLINORIL. This may be due to fluid
retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on
long-term treatment with NSAIDs, including CLINORIL, should have their hemoglobin or hematocrit checked if
they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike
aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients
receiving CLINORIL who may be adversely affected by alterations in platelet function, such as those with
coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive
asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such
aspirin-sensitive patients, CLINORIL should not be administered to patients with this form of aspirin sensitivity
and should be used with caution in patients with preexisting asthma.
Renal Calculi
Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in
association with other calculus components. CLINORIL should be used with caution in patients with a history of
renal lithiasis, and they should be kept well hydrated while receiving CLINORIL.
Pancreatitis
Pancreatitis has been reported in patients receiving CLINORIL (see ADVERSE REACTIONS). Should
pancreatitis be suspected, the drug should be discontinued and not restarted, supportive medical therapy
instituted, and the patient monitored closely with appropriate laboratory studies (e.g., serum and urine amylase,
amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase, etc.). A search for other causes
of pancreatitis as well as those conditions which mimic pancreatitis should be conducted.
Ocular Effects
Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is recommended
that patients who develop eye complaints during treatment with CLINORIL have ophthalmologic studies.
Hepatic Insufficiency
In patients with poor liver function, delayed, elevated and prolonged circulating levels of the sulfide and
sulfone metabolites may occur. Such patients should be monitored closely; a reduction of daily dosage may be
required.
SLE and Mixed Connective Tissue Disease
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, there may be an
increased risk of aseptic meningitis (see ADVERSE REACTIONS).
Information for Patients
Patients should be informed of the following information before initiating therapy with an NSAID and
periodically during the course of ongoing therapy. Patients should also be encouraged to read the
NSAID Medication Guide that accompanies each prescription dispensed.
1. CLINORIL, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which
may result in hospitalization and even death. Although serious CV events can occur without
warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any
indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see
WARNINGS, CARDIOVASCULAR EFFECTS).
2. CLINORIL, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such
as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI
tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for
the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when
observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and
hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-070
Page 11
3. CLINORIL, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis,
SJS, and TEN, which may result in hospitalizations and even death. Although serious skin
reactions may occur without warning, patients should be alert for the signs and symptoms of skin
rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for
medical advice when observing any indicative signs or symptoms. Patients should be advised to
stop the drug immediately if they develop any type of rash and contact their physicians as soon as
possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty
breathing, swelling of the face or throat). If these occur, patients should be instructed to seek
immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, CLINORIL should be avoided because it may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should
monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their
CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal
disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or
worsen, CLINORIL should be discontinued.
Drug Interactions
ACE-Inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II
antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with
ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the co-
administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further
deterioration of renal function, including possible acute renal failure, which is usually reversible.
Acetaminophen
Acetaminophen had no effect on the plasma levels of sulindac or its sulfide metabolite.
Aspirin
The concomitant administration of aspirin with sulindac significantly depressed the plasma levels of the
active sulfide metabolite. A double-blind study compared the safety and efficacy of CLINORIL 300 or 400 mg
daily given alone or with aspirin 2.4 g/day for the treatment of osteoarthritis. The addition of aspirin did not alter
the types of clinical or laboratory adverse experiences for CLINORIL; however, the combination showed an
increase in the incidence of gastrointestinal adverse experiences. Since the addition of aspirin did not have a
favorable effect on the therapeutic response to CLINORIL, the combination is not recommended.
Cyclosporine
Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated
with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin.
NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully
monitored.
Diflunisal
The concomitant administration of CLINORIL and diflunisal in normal volunteers resulted in lowering of the
plasma levels of the active sulindac sulfide metabolite by approximately one-third.
Diuretics
Clinical studies, as well as post marketing observations, have shown that CLINORIL can reduce the
natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-070
Page 12
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely
for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
DMSO
DMSO should not be used with sulindac. Concomitant administration has been reported to reduce the
plasma levels of the active sulfide metabolite and potentially reduce efficacy. In addition, this combination has
been reported to cause peripheral neuropathy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The
mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately
20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus,
when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of
lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This
may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are
administered concomitantly with methotrexate.
NSAIDs
The concomitant use of CLINORIL with other NSAIDs is not recommended due to the increased possibility of
gastrointestinal toxicity, with little or no increase in efficacy.
Oral anticoagulants
Although sulindac and its sulfide metabolite are highly bound to protein, studies in which CLINORIL was
given at a dose of 400 mg daily have shown no clinically significant interaction with oral anticoagulants.
However, patients should be monitored carefully until it is certain that no change in their anticoagulant dosage is
required. Special attention should be paid to patients taking higher doses than those recommended and to
patients with renal impairment or other metabolic defects that might increase sulindac blood levels. The effects
of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of
serious GI bleeding higher than users of either drug alone.
Oral hypoglycemic agents
Although sulindac and its sulfide metabolite are highly bound to protein, studies in which CLINORIL was
given at a dose of 400 mg daily, have shown no clinically significant interaction with oral hypoglycemic agents.
However, patients should be monitored carefully until it is certain that no change in their hypoglycemic dosage is
required. Special attention should be paid to patients taking higher doses than those recommended and to
patients with renal impairment or other metabolic defects that might increase sulindac blood levels.
Probenecid
Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma
levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the
uricosuric action of probenecid, which probably is not significant under most circumstances.
Propoxyphene hydrochloride
Propoxyphene hydrochloride had no effect on the plasma levels of sulindac or its sulfide metabolite.
Pregnancy
Teratogenic Effects. Pregnancy Category C.
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental
abnormalities. However, animal reproduction studies are not always predictive of human response. There are no
adequate and well-controlled studies in pregnant women. CLINORIL should be used in pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system
(closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include:
constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-
closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial
degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or
failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios,
gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.
In reproduction studies in the rat, a decrease in average fetal weight and an increase in numbers of dead
pups were observed on the first day of the postpartum period at dosage levels of 20 and 40 mg/kg/day (2½ and
5 times the usual maximum daily dose in humans), although there was no adverse effect on the survival and
growth during the remainder of the postpartum period. CLINORIL prolongs the duration of gestation in rats, as
This label may not be the latest approved by FDA.
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NDA 17-911/S-070
Page 13
do other compounds of this class. Visceral and skeletal malformations observed in low incidence among rabbits
in some teratology studies did not occur at the same dosage levels in repeat studies, nor at a higher dosage
level in the same species.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of CLINORIL on
labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk; however, it is secreted in the milk of lactating
rats. Because many drugs are excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from CLINORIL, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing
age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or
bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population
(see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
CLINORIL is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may
be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection and it may be useful to monitor renal function (see
WARNINGS, Renal Effects).
ADVERSE REACTIONS
The following adverse reactions were reported in clinical trials or have been reported since the drug was
marketed. The probability exists of a causal relationship between CLINORIL and these adverse reactions. The
adverse reactions which have been observed in clinical trials encompass observations in 1,865 patients,
including 232 observed for at least 48 weeks.
Incidence Greater Than 1%
Gastrointestinal
The most frequent types of adverse reactions occurring with CLINORIL are gastrointestinal; these include
gastrointestinal pain (10%), dyspepsia***, nausea*** with or without vomiting, diarrhea***, constipation***,
flatulence, anorexia and gastrointestinal cramps.
Dermatologic
Rash***, pruritus.
Central Nervous System
Dizziness***, headache***, nervousness.
Special Senses
Tinnitus.
Miscellaneous
Edema (see WARNINGS).
Incidence Less Than 1 in 100
Gastrointestinal
Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI
perforation and intestinal strictures (diaphragms) have been reported rarely.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.
There have been rare reports of sulindac metabolites in common bile duct "sludge" and in biliary calculi in
patients with symptoms of cholecystitis who underwent a cholecystectomy.
Pancreatitis (see PRECAUTIONS).
Ageusia; glossitis.
Dermatologic
Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.
Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis have
been reported.
*** Incidence between 3% and 9%. Those reactions occurring in 1% to 3% of patients are not marked with an asterisk.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-070
Page 14
Cardiovascular
Congestive heart failure, especially in patients with marginal cardiac function; palpitation; hypertension.
Hematologic
Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow
depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on oral
anticoagulants (see PRECAUTIONS).
Genitourinary
Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including
renal failure; interstitial nephritis; nephrotic syndrome.
Renal calculi containing sulindac metabolites have been observed rarely.
Metabolic
Hyperkalemia.
Musculoskeletal
Muscle weakness.
Psychiatric
Depression; psychic disturbances including acute psychosis.
Nervous System
Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis (especially in patients
with systemic lupus erythematosus (SLE) and mixed connective tissue disease, see PRECAUTIONS)..
Special Senses
Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste.
Respiratory
Epistaxis.
Hypersensitivity Reactions
Anaphylaxis; angioneurotic edema; bronchial spasm; dyspnea.
Hypersensitivity vasculitis.
A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include
constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic
reactions ⎯ see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic
failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis,
eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and
other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain,
tachycardia).
Causal Relationship Unknown
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic
streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, sometimes
with fatal outcome (see also PRECAUTIONS, General).
Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under
circumstances where a causal relationship could not be established. However, in these rarely reported events,
that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to
physicians.
Cardiovascular
Arrhythmia.
Metabolic
Hyperglycemia.
Nervous System
Neuritis.
Special Senses
Disturbances of the retina and its vasculature.
Miscellaneous
Gynecomastia.
MANAGEMENT OF OVERDOSAGE
Cases of overdosage have been reported and rarely, deaths have occurred. The following signs and
symptoms may be observed following overdosage: stupor, coma, diminished urine output and hypotension.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-070
Page 15
In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and
the patient carefully observed and given symptomatic and supportive treatment.
Animal studies show that absorption is decreased by the prompt administration of activated charcoal and
excretion is enhanced by alkalinization of the urine.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of CLINORIL and other treatment options before deciding
to use CLINORIL. Use the lowest effective dose for the shortest duration consistent with individual patient
treatment goals (see WARNINGS).
After observing the response to initial therapy with CLINORIL, the dose and frequency should be adjusted to
suit an individual patient’s needs.
CLINORIL should be administered orally twice a day with food. The maximum dosage is 400 mg per day.
Dosages above 400 mg per day are not recommended.
In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended starting dosage is
150 mg twice a day. The dosage may be lowered or raised depending on the response.
A prompt response (within one week) can be expected in about one-half of patients with osteoarthritis,
ankylosing spondylitis, and rheumatoid arthritis. Others may require longer to respond.
In acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis) and acute gouty arthritis, the
recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may
be reduced according to the response. In acute painful shoulder, therapy for 7-14 days is usually adequate. In
acute gouty arthritis, therapy for 7 days is usually adequate.
HOW SUPPLIED
No. 3360 ⎯ Tablets CLINORIL 150 mg are bright yellow, hexagon-shaped, compressed tablets, coded
MSD 941 on one side and CLINORIL on the other. They are supplied as follows:
NDC 0006-0941-68 in bottles of 100.
No. 3353X ⎯ Tablets CLINORIL 200 mg are bright yellow, hexagon-shaped, compressed tablets, one side
full scored, the other side half scored and debossed MSD 942. They are supplied as follows:
NDC 0006-0942-68 in bottles of 100.
Storage
Store in a well-closed container at room temperature 15-30ºC (59-86ºF).
Rx Only
Manufactured for:
By:
MERCK SHARP & DOHME Pty., Ltd.
South Granville, NSW, Australia 2142.
Issued February 2007
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-070
Page 16
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead
to death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at
any time during treatment.
Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from
medical conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any
other NSAID medicine
• for pain right before or after heart bypass surgery
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-070
Page 17
Tell your healthcare provider:
• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can
interact with each other and cause serious side effects. Keep a list of your
medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women
late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid
retention)
• kidney problems including kidney
failure
• bleeding and ulcers in the stomach
and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have
asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble
breathing
• slurred speech
• chest pain
• swelling of the face or
throat
• weakness in one part or side of your
body
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• there is blood in your
bowel movement or it is
black and sticky like tar
• your skin or eyes look yellow
• unusual weight gain
• stomach pain
• flu-like symptoms
• skin rash or blisters with
fever
• vomit blood
• swelling of the arms and
legs, hands and feet
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-911/S-070
Page 18
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack.
Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also
cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-
the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs
for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbiprofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethegan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan,
Naprapac (copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is
usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term
continuous use may increase the risk of heart attack or stroke.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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11,092
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*
10159300
barcode
barcode
ORTHO-NOVUM® Tablets
(norethindrone/ethinyl estradiol)
and MODICON® Tablets
(norethindrone/ethinyl estradiol)
Patients should be counseled that this product does not
protect against HIV infection (AIDS) and other sexually
transmitted diseases.
barcode
barcode
COMBINATION ORAL CONTRACEPTIVES
Each of the following products is a combination oral contraceptive containing the prog
estational compound norethindrone and the estrogenic compound ethinyl estradiol.
ORTHO-NOVUM® 7/7/7 Tablets: Each white tablet contains 0.5 mg of norethindrone
and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium
stearate and pregelatinized corn starch. Each light peach tablet contains 0.75 mg of
norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow
No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each peach tablet
contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients
include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn
starch. Each green tablet contains only inert ingredients, as follows: D&C Yellow No.
10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate,
microcrystalline cellulose and pregelatinized corn starch.
ORTHO-NOVUM® 1/35 Tablets: Each peach tablet contains 1 mg of norethindrone
and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lac
tose, magnesium stearate and pregelatinized corn starch. Each green tablet contains
only inert ingredients, as listed under green tablets in ORTHO-NOVUM 7/7/7.
MODICON® Tablets: Each white tablet contains 0.5 mg of norethindrone and 0.035 mg
of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and prege
latinized corn starch. Each green tablet contains only inert ingredients, as listed under
green tablets in ORTHO-NOVUM 7/7/7.
The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3
one, for ethinyl estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their
structural formulas are as follows: chemical structure
CLINICAL PHARMACOLOGY
COMBINATION ORAL CONTRACEPTIVES
Combination oral contraceptives act by suppression of gonadotropins. Although the
primary mechanism of this action is inhibition of ovulation, other alterations include
changes in the cervical mucus (which increase the difficulty of sperm entry into the
uterus) and the endometrium (which reduce the likelihood of implantation).
INDICATIONS AND USAGE
ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON Tablets are indicated
for the prevention of pregnancy in women who elect to use this product as a method
of contraception.
Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy
rates for users of combination oral contraceptives and other methods of contracep
tion. The efficacy of these contraceptive methods, except sterilization, the IUD, and
the NORPLANT® System depends upon the reliability with which they are used. Correct
and consistent use of methods can result in lower failure rates.
Table I: Percentage of Women Experiencing an Unintended Pregnancy
During the First Year of Typical Use
and the First Year of Perfect Use of Contraception
and the Percentage Continuing Use
at the End of the First Year. United States.
% of Women Experiencing an
% of Women
Unintended Pregnancy
Continuing Use
within the First Year of Use
at One Year3
Method
Typical Use1
Perfect Use2
(1)
(2)
(3)
(4)
Chance4
85
85
Spermicides5
26
6
40
Periodic abstinence
25
63
Calendar
9
Ovulation Method
3
Sympto-Thermal6
2
Post-Ovulation
1
Cap7
Parous Women
40
26
42
Nulliparous Women
20
9
56
Sponge
Parous Women
40
20
42
Nulliparous Women
20
9
56
Diaphragm7
20
6
56
Withdrawal
19
4
Condom8
Female (Reality®)
21
5
56
Male
14
3
61
Pill
5
71
Progestin Only
0.5
Combined
0.1
IUD
Progesterone T
2.0
1.5
81
Copper T380A
0.8
0.6
78
LNg 20
0.1
0.1
81
Depo-Provera®
0.3
0.3
70
Norplant® and Norplant-2®
0.05
0.05
88
Female Sterilization
0.5
0.5
100
Male Sterilization
0.15
0.10
100
Adapted from Hatcher et al, 1998, Ref. #1.
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected
intercourse reduces the risk of pregnancy by at least 75%.9
Lactational Amenorrhea Method: LAM is highly effective, temporary method of con
traception.10
Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates
W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised
Edition. New York NY: Irvington Publishers, 1998.
1 Among typical couples who initiate use of a method (not necessarily for the first time),
the percentage who experience an accidental pregnancy during the first year if they do not
stop use for any other reason.
2 Among couples who initiate use of a method (not necessarily for the first time) and who
use it perfectly (both consistently and correctly), the percentage who experience an acci
dental pregnancy during the first year if they do not stop use for any other reason.
3 Among couples attempting to avoid pregnancy, the percentage who continue to use a
method for one year.
4 The percents becoming pregnant in columns (2) and (3) are based on data from popula
tions where contraception is not used and from women who cease using contraception in
order to become pregnant. Among such populations, about 89% become pregnant within
one year. This estimate was lowered slightly (to 85%) to represent the percent who would
become pregnant within one year among women now relying on reversible methods of
contraception if they abandoned contraception altogether.
5 Foams, creams, gels, vaginal suppositories, and vaginal film.
6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and
basal body temperature in the post-ovulatory phases.
7 With spermicidal cream or jelly.
8 Without spermicides.
9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and
a second dose 12 hours after the first dose. The Food and Drug Administration has
declared the following brands of oral contraceptives to be safe and effective for emergency
contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or
Levlen® (1 dose is 2 light-orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or
Tri-Levlen® (1 dose is 4 yellow pills).
10However, to maintain effective protection against pregnancy, another method of
contraception must be used as soon as menstruation resumes, the frequency or duration
of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of
age.
ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35 and MODICON have not been studied
for and are not indicated for use in emergency contraception.
CONTRAINDICATIONS
Oral contraceptives should not be used in women who currently have the following
conditions:
• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Cerebral vascular or coronary artery disease (current or history)
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Known or suspected carcinoma of the breast
• Carcinoma of the endometrium or other known or suspected estrogen-dependent
neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Acute or chronic hepatocellular disease with abnormal liver function
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Hypersensitivity to any component of this product
WARNINGS
Cigarette smoking increases the risk of serious cardiovascular side
effects from oral contraceptive use. This risk increases with age and with
heavy smoking (15 or more cigarettes per day) and is quite marked in
women over 35 years of age. Women who use oral contraceptives should
be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risks of several serious
conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia,
and gallbladder disease, although the risk of serious morbidity or mortality is very small
in healthy women without underlying risk factors. The risk of morbidity and mortality
increases significantly in the presence of other underlying risk factors such as hyper
tension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following
information relating to these risks.
The information contained in this package insert is principally based on studies carried
out in patients who used oral contraceptives with higher formulations of estrogens and
progestogens than those in common use today. The effect of long-term use of the oral
contraceptives with lower formulations of both estrogens and progestogens remains
to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retro
spective or case control studies and prospective or cohort studies. Case control studies
provide a measure of the relative risk of a disease, namely, a ratio of the incidence of
a disease among oral contraceptive users to that among nonusers. The relative risk
does not provide information on the actual clinical occurrence of a disease. Cohort
studies provide a measure of attributable risk, which is the difference in the incidence
of disease between oral contraceptive users and nonusers. The attributable risk does
provide information about the actual occurrence of a disease in the population (adapted
from refs. 2 and 3 with the author’s permission). For further information, the reader is
referred to a text on epidemiological methods.
1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS
a. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to oral contraceptive
use. This risk is primarily in smokers or women with other underlying risk factors for
coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity,
and diabetes. The relative risk of heart attack for current oral contraceptive users has
been estimated to be two to six.4-10 The risk is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute sub
stantially to the incidence of myocardial infarctions in women in their mid-thirties or
older with smoking accounting for the majority of excess cases.11 Mortality rates as
sociated with circulatory disease have been shown to increase substantially in smokers,
especially in those 35 years of age and older and in nonsmokers over the age of 40
among women who use oral contraceptives.
TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS
BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS
BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE
(Adapted from P.M. Layde and V. Beral, ref. #12.)
Oral contraceptives may compound the effects of well-known risk factors, such as hy
pertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progesto
gens are known to decrease HDL cholesterol and cause glucose intolerance, while
estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been
shown to increase blood pressure among users (see Section 9 in WARNINGS). Similar
effects on risk factors have been associated with an increased risk of heart disease.
Oral contraceptives must be used with caution in women with cardiovascular disease
risk factors.
b. Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the use
of oral contraceptives is well established. Case control studies have found the relative
risk of users compared to nonusers to be 3 for the first episode of superficial venous
thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for
women with predisposing conditions for venous thromboembolic disease.2,3,19-24 Cohort
studies have shown the relative risk to be somewhat lower, about 3 for new cases and
about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic dis
ease associated with oral contraceptives is not related to length of use and disappears
after pill use is stopped.2
A two- to four-fold increase in relative risk of post-operative thromboembolic compli
cations has been reported with the use of oral contraceptives.9 The relative risk of ve
nous thrombosis in women who have predisposing conditions is twice that of women
without such medical conditions.26 If feasible, oral contraceptives should be discon
tinued at least four weeks prior to and for two weeks after elective surgery of a type
associated with an increase in risk of thromboembolism and during and following pro
longed immobilization. Since the immediate postpartum period is also associated with
an increased risk of thromboembolism, oral contraceptives should be started no ear
lier than four weeks after delivery in women who elect not to breast feed.
c. Cerebrovascular diseases
Oral contraceptives have been shown to increase both the relative and attributable
risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in gen
eral, the risk is greatest among older (>35 years), hypertensive women who also smoke.
Hypertension was found to be a risk factor for both users and nonusers, for both types
of strokes, and smoking interacted to increase the risk of stroke.27-29
In a large study, the relative risk of thrombotic strokes has been shown to range from
3 for normotensive users to 14 for users with severe hypertension.30 The relative risk
of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contra
ceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who
used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe
hypertension.30 The attributable risk is also greater in older women.3
d. Dose-related risk of vascular disease from oral contraceptives
A positive association has been observed between the amount of estrogen and progesto
gen in oral contraceptives and the risk of vascular disease.31-33 A decline in serum high
density lipoproteins (HDL) has been reported with many progestational agents.14-16 A
decline in serum high density lipoproteins has been associated with an increased in
cidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the
net effect of an oral contraceptive depends on a balance achieved between doses of
estrogen and progestogen and the activity of the progestogen used in the contracep
tives. The activity and amount of both hormones should be considered in the choice
of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles
of therapeutics. For any particular estrogen/progestogen combination, the dosage reg
imen prescribed should be one which contains the least amount of estrogen and
progestogen that is compatible with a low failure rate and the needs of the individual
patient. New acceptors of oral contraceptive agents should be started on preparations
containing the lowest estrogen content which is judged appropriate for the
individual patient.
e. Persistence of risk of vascular disease
There are two studies which have shown persistence of risk of vascular disease for
ever-users of oral contraceptives. In a study in the United States, the risk of develop
ing myocardial infarction after discontinuing oral contraceptives persists for at least 9
years for women 40-49 years who had used oral contraceptives for five or more years,
but this increased risk was not demonstrated in other age groups.8 In another study in
Great Britain, the risk of developing cerebrovascular disease persisted for at least 6
years after discontinuation of oral contraceptives, although excess risk was very small.34
10159300
ORTHO-NOVUM® Tablets
(norethindrone/ethinyl estradiol)
and MODICON® Tablets
(norethindrone/ethinyl estradiol)
Patients should be counseled that this product does not
protect against HIV infection (AIDS) and other sexually
transmitted diseases.
However, both studies were performed with oral contraceptive formulations contain
ing 50 micrograms or higher of estrogens.
2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE
One study gathered data from a variety of sources which have estimated the mortality
rate associated with different methods of contraception at different ages (Table III). These
estimates include the combined risk of death associated with contraceptive methods
plus the risk attributable to pregnancy in the event of method failure. Each method of
contraception has its specific benefits and risks. The study concluded that with the
exception of oral contraceptive users 35 and older who smoke, and 40 and older who
do not smoke, mortality associated with all methods of birth control is low and below
that associated with childbirth. The observation of an increase in risk of mortality with
age for oral contraceptive users is based on data gathered in the 1970’s.35 Current clin
ical recommendation involves the use of lower estrogen dose formulations and a care
ful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs
Advisory Committee was asked to review the use of oral contraceptives in women 40
years of age and over. The Committee concluded that although cardiovascular disease
risks may be increased with oral contraceptive use after age 40 in healthy non-smok
ing women (even with the newer low-dose formulations), there are also greater po
tential health risks associated with pregnancy in older women and with the alternative
surgical and medical procedures which may be necessary if such women do not have
access to effective and acceptable means of contraception. The Committee recom
mended that the benefits of low-dose oral contraceptive use by healthy non-smoking
women over 40 may outweigh the possible risks.
Of course, older women, as all women who take oral contraceptives, should take an
oral contraceptive which contains the least amount of estrogen and progestogen that
is compatible with a low failure rate and individual patient needs.
TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS
ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN,
BY FERTILITY CONTROL METHOD ACCORDING TO AGE
Method of control
15-19
20-24
25-29
30-34
35-39
40-44
and outcome
No fertility
7.0
7.4
9.1
14.8
25.7
28.2
control methods*
Oral contraceptives
0.3
0.5
0.9
1.9
13.8
31.6
non-smoker**
Oral contraceptives
2.2
3.4
6.6
13.5
51.1
117.2
smoker**
IUD**
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/
1.9
1.2
1.2
1.3
2.2
2.8
spermicide*
Periodic
2.5
1.6
1.6
1.7
2.9
3.6
abstinence*
*Deaths are birth-related
**Deaths are method-related
Adapted from H.W. Ory, ref. #35.
3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS
Numerous epidemiological studies have been performed on the incidence of breast,
endometrial, ovarian and cervical cancer in women using oral contraceptives. The risk
of having breast cancer diagnosed may be slightly increased among current and re
cent users of COCs. However, this excess risk appears to decrease over time after
COC discontinuation and by 10 years after cessation the increased risk disappears.
Some studies report an increased risk with duration of use while other studies do not
and no consistent relationships have been found with dose or type of steroid. Some
studies have found a small increase in risk for women who first use COCs before age
20. Most studies show a similar pattern of risk with COC use regardless of a woman’s
reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous OC users tend to be less clinically ad
vanced than in nonusers.
Women who currently have or have had breast cancer should not use oral contracep
tives because breast cancer is usually a hormonally-sensitive tumor.
Some studies suggest that oral contraceptive use has been associated with an increase
in the risk of cervical intraepithelial neoplasia in some populations of women.45-48
However, there continues to be controversy about the extent to which such findings
may be due to differences in sexual behavior and other factors.
In spite of many studies of the relationship between oral contraceptive use and breast
and cervical cancers, a cause-and-effect relationship has not been established.
4. HEPATIC NEOPLASIA
Benign hepatic adenomas are associated with oral contraceptive use, although the in
cidence of benign tumors is rare in the United States. Indirect calculations have esti
mated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that
increases after four or more years of use especially with oral contraceptives of higher
dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdom
inal hemorrhage.50,51
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma
in long-term (>8 years) oral contraceptive users. However, these cancers are extremely
rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral
contraceptive users approaches less than one per million users.
5. OCULAR LESIONS
There have been clinical case reports of retinal thrombosis associated with the use of
oral contraceptives. Oral contraceptives should be discontinued if there is unexplained
partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or reti
nal vascular lesions. Appropriate diagnostic and therapeutic measures should be un
dertaken immediately.
6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY
Extensive epidemiological studies have revealed no increased risk of birth defects in
women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent
studies also do not indicate a teratogenic effect, particularly in so far as cardiac anom
alies and limb reduction defects are concerned,55,56,58,59 when taken inadvertently dur
ing early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not be
used as a test for pregnancy. Oral contraceptives should not be used during pregnancy
to treat threatened or habitual abortion.
It is recommended that for any patient who has missed two consecutive periods,
pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule,
the possibility of pregnancy should be considered at the time of the first missed pe
riod. Oral contraceptive use should be discontinued if pregnancy is confirmed.
7. GALLBLADDER DISEASE
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery
in users of oral contraceptives and estrogens.60,61 More recent studies, however, have
shown that the relative risk of developing gallbladder disease among oral contracep
tive users may be minimal.62-64 The recent findings of minimal risk may be related to
the use of oral contraceptive formulations containing lower hormonal doses of estro
gens and progestogens.
8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS
Oral contraceptives have been shown to cause a decrease in glucose tolerance in a
significant percentage of users.17 This effect has been shown to be directly related to
estrogen dose.65 Progestogens increase insulin secretion and create insulin resistance,
this effect varying with different progestational agents.17,66 However, in the non-dia
betic woman, oral contraceptives appear to have no effect on fasting blood glucose.67
Because of these demonstrated effects, prediabetic and diabetic women in particular
should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill.
As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and
lipoprotein levels have been reported in oral contraceptive users.
9. ELEVATED BLOOD PRESSURE
Women with significant hypertension should not be started on hormonal contracep
tion.92 An increase in blood pressure has been reported in women taking oral contra
ceptives68 and this increase is more likely in older oral contraceptive users69 and with
extended duration of use.61 Data from the Royal College of General Practitioners12 and
subsequent randomized trials have shown that the incidence of hypertension increases
with increasing progestational activity.
Women with a history of hypertension or hypertension-related diseases, or renal
disease70 should be encouraged to use another method of contraception. If women
elect to use oral contraceptives, they should be monitored closely and if significant el
evation of blood pressure occurs, oral contraceptives should be discontinued. For most
women, elevated blood pressure will return to normal after stopping oral contraceptives,
and there is no difference in the occurrence of hypertension between former and never
users.68-71
10. HEADACHE
The onset or exacerbation of migraine or development of headache with a new pattern
which is recurrent, persistent or severe requires discontinuation of oral contraceptives
and evaluation of the cause.
11. BLEEDING IRREGULARITIES
Breakthrough bleeding and spotting are sometimes encountered in patients on oral
contraceptives, especially during the first three months of use. Nonhormonal causes
should be considered and adequate diagnostic measures taken to rule out malignancy
or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal
vaginal bleeding. If pathology has been excluded, time or a change to another formu
lation may solve the problem. In the event of amenorrhea, pregnancy should be ruled
out.
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when
such a condition was preexistent.
12. ECTOPIC PREGNANCY
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
1. GENERAL
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
2. PHYSICAL EXAMINATION AND FOLLOW UP
It is good medical practice for all women to have annual history and physical examinations,
including women using oral contraceptives. The physical examination, however, may
be deferred until after initiation of oral contraceptives if requested by the woman and
judged appropriate by the clinician. The physical examination should include special
reference to blood pressure, breasts, abdomen and pelvic organs, including cervical
cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent
abnormal vaginal bleeding, appropriate measures should be conducted to rule out
malignancy. Women with a strong family history of breast cancer or who have breast
nodules should be monitored with particular care.
3. LIPID DISORDERS
Women who are being treated for hyperlipidemias should be followed closely if they
elect to use oral contraceptives. Some progestogens may elevate LDL levels and may
render the control of hyperlipidemias more difficult.
4. LIVER FUNCTION
If jaundice develops in any woman receiving such drugs, the medication should be dis
continued. Steroid hormones may be poorly metabolized in patients with impaired liver
function.
5. FLUID RETENTION
Oral contraceptives may cause some degree of fluid retention. They should be prescribed
with caution, and only with careful monitoring, in patients with conditions which might
be aggravated by fluid retention.
6. EMOTIONAL DISORDERS
Women with a history of depression should be carefully observed and the drug
discontinued if depression recurs to a serious degree.
7. CONTACT LENSES
Contact lens wearers who develop visual changes or changes in lens tolerance should
be assessed by an ophthalmologist.
8. DRUG INTERACTIONS
Changes in contraceptive effectiveness associated with co-administration of
other products:
Contraceptive effectiveness may be reduced when hormonal contraceptives are co
administered with antibiotics, anticonvulsants, and other drugs that increase the
metabolism of contraceptive steroids. This could result in unintended pregnancy or
breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone,
phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and
bosentan. Several cases of contraceptive failure and breakthrough bleeding have been
reported in the literature with concomitant administration of antibiotics such as ampi
cillin and tetracyclines. However, clinical pharmacology studies investigating drug in
teraction between combined oral contraceptives and these antibiotics have reported
inconsistent results.
Several of the anti-HIV protease inhibitors have been studied with co-administration
of oral combination hormonal contraceptives; significant changes (increase and de
crease) in the plasma levels of the estrogen and progestin have been noted in some
cases. The safety and efficacy of oral contraceptive products may be affected with co
administration of anti-HIV protease inhibitors. Healthcare professionals should refer to
the label of the individual anti-HIV protease inhibitors for further drug-drug interaction
information.
Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic
enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the ef
fectiveness of contraceptive steroids. This may also result in breakthrough bleeding.
Concurrent use of bosentan and norethisterone/ethinyl estradiol may result in de
creased concentrations of these contraceptive hormones thereby increasing the risk
of unintended pregnancy and unscheduled bleeding.
Increase in plasma levels associated with co-administered drugs:
Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estra
diol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid
and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition
of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase
plasma hormone levels.
Changes in plasma levels of co-administered drugs:
Combination hormonal contraceptives containing some synthetic estrogens (e.g.,
ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma
concentrations of cyclosporin, prednisolone, and theophylline have been reported with
concomitant administration of oral contraceptives. Decreased plasma concentrations
of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and
clofibric acid, due to induction of conjugation, have been noted when these drugs were
administered with oral contraceptives.
Combined hormonal contraceptives have been shown to significantly decrease plasma
concentrations of lamotrigine when co-administered due to induction of lamotrigine
glucuronidation. This may reduce seizure control; therefore, dosage adjustments of
lamotrigine may be necessary.95
Healthcare professionals are advised to also refer to prescribing information of co-ad
ministered drugs for recommendations regarding management of concomitant therapy.
9. INTERACTIONS WITH LABORATORY TESTS
Certain endocrine and liver function tests and blood components may be affected by
oral contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; in
creased norepinephrine-induced platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid
hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioim
munoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4
concentration is unaltered.
c. Other binding proteins may be elevated in serum.
d. Sex-binding globulins are increased and result in elevated levels of total circulating
sex steroids and corticoids; however, free or biologically active levels remain
unchanged.
e. Triglycerides may be increased and levels of various other lipids and lipoproteins
may be affected.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive therapy. This may be
of clinical significance if a woman becomes pregnant shortly after discontinuing oral
contraceptives.
10. CARCINOGENESIS
See WARNINGS Section.
11. PREGNANCY
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS Sections.
12. NURSING MOTHERS
Small amounts of oral contraceptive steroids have been identified in the milk of nursing
mothers and a few adverse effects on the child have been reported, including jaundice
and breast enlargement. In addition, combination oral contraceptives given in the post
partum period may interfere with lactation by decreasing the quantity and quality of
breast milk. If possible, the nursing mother should be advised not to use combination
oral contraceptives but to use other forms of contraception until she has completely
weaned her child.
13. PEDIATRIC USE
Safety and efficacy of ORTHO-NOVUM Tablets and MODICON Tablets has been
established in women of reproductive age. Safety and efficacy are expected to be the
same for postpubertal adolescents under the age of 16 and for users 16 years and
older. Use of this product before menarche is not indicated.
14. GERIATRIC USE
This product has not been studied in women over 65 years of age and is not indicated
in this population.
INFORMATION FOR THE PATIENT
See Patient Labeling printed below.
ADVERSE REACTIONS
An increased risk of the following serious adverse reactions has been associated with
the use of oral contraceptives (See WARNINGS Section).
• Thrombophlebitis and venous thrombosis with or without embolism
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the use of
oral contraceptives:
• Mesenteric thrombosis
• Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral contra
ceptives and are believed to be drug-related:
• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Allergic reaction, including rash, urticaria, angioedema
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses
The following adverse reactions have been reported in users of oral contraceptives and
a causal association has been neither confirmed nor refuted:
• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Acne
• Changes in libido
• Colitis
• Budd-Chiari Syndrome
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
oral contraceptives by young children. Overdosage may cause nausea, and withdrawal
bleeding may occur in females.
NON-CONTRACEPTIVE HEALTH BENEFITS
The following non-contraceptive health benefits related to the use of combination oral
contraceptives are supported by epidemiological studies which largely utilized oral con
traceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estra
diol or 0.05 mg mestranol.73-78
Effects on menses:
• increased menstrual cycle regularity
• decreased blood loss and decreased incidence of iron deficiency anemia
• decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
• decreased incidence of functional ovarian cysts
• decreased incidence of ectopic pregnancies
Other effects:
• decreased incidence of fibroadenomas and fibrocystic disease of the breast
• decreased incidence of acute pelvic inflammatory disease
• decreased incidence of endometrial cancer
• decreased incidence of ovarian cancer
DOSAGE AND ADMINISTRATION
To achieve maximum contraceptive effectiveness, ORTHO-NOVUM Tablets and
MODICON Tablets must be taken exactly as directed and at intervals not exceeding
24 hours. ORTHO-NOVUM Tablets and MODICON Tablets are available in the DIALPAK®
Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also available.
Sunday Start
When taking ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON, the first
“active” tablet should be taken on the first Sunday after menstruation begins. If period
begins on Sunday, the first “active” tablet should be taken that day. Take one active
tablet daily for 21 days followed by one green “reminder” tablet daily for 7 days. After
28 tablets have been taken, a new course is started the next day (Sunday). For the first
cycle of a Sunday Start regimen, another method of contraception should be used until
after the first 7 consecutive days of administration.
If the patient misses one (1) “active” tablet in Weeks 1, 2, or 3, the tablet should be
taken as soon as she remembers. If the patient misses two (2) “active” tablets in Week 1
or Week 2, the patient should take two (2) tablets the day she remembers and two (2)
tablets the next day; and then continue taking one (1) tablet a day until she finishes the
pack. The patient should be instructed to use a back-up method of birth control such
as condoms or spermicide if she has sex in the seven (7) days after missing pills. If the
patient misses two (2) “active” tablets in the third week or misses three (3) or more “ac
tive” tablets in a row, the patient should continue taking one tablet every day until
Sunday. On Sunday the patient should throw out the rest of the pack and start a new
pack that same day. The patient should be instructed to use a back-up method of birth
control if she has sex in the seven (7) days after missing pills.
Complete instructions to facilitate patient counseling on proper pill usage may be found
in the Detailed Patient Labeling (“How to Take the Pill” section).
Day 1 Start
The dosage of ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON, for the
initial cycle of therapy is one “active” tablet administered daily from the 1st through
the 21st day of the menstrual cycle, counting the first day of menstrual flow as “Day
1” followed by one green “reminder” tablet daily for 7 days. Tablets are taken without
interruption for 28 days. After 28 tablets have been taken, a new course is started the
next day.
If the patient misses one (1) “active” tablet in Weeks 1, 2, or 3, the tablet should be
taken as soon as she remembers. If the patient misses two (2) “active” tablets in Week 1
or Week 2, the patient should take two (2) tablets the day she remembers and two (2)
tablets the next day; and then continue taking one (1) tablet a day until she finishes the
pack. The patient should be instructed to use a back-up method of birth control such
as condoms or spermicide if she has sex in the seven (7) days after missing pills. If the
patient misses two (2) “active” tablets in the third week or misses three (3) or more “ac
tive” tablets in a row, the patient should throw out the rest of the pack and start a new
pack that same day. The patient should be instructed to use a back-up method of birth
control if she has sex in the seven (7) days after missing pills.
Complete instructions to facilitate patient counseling on proper pill usage may be found
in the Detailed Patient Labeling (“How to Take the Pill” section).
The use of ORTHO-NOVUM 7/7/7, ORTHO-NOVUM 1/35, and MODICON for contra
ception may be initiated 4 weeks postpartum in women who elect not to breast feed.
When the tablets are administered during the postpartum period, the increased risk
of thromboembolic disease associated with the postpartum period must be consid
ered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic dis
ease. See also PRECAUTIONS for “Nursing Mothers.”) The possibility of ovulation and
conception prior to initiation of medication should be considered.
(See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.)
ADDITIONAL INSTRUCTIONS
Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients
discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular
bleeding from the vagina, nonfunctional causes should be borne in mind. In undiag
nosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnos
tic measures are indicated to rule out pregnancy or malignancy. If pathology has been
excluded, time or a change to another formulation may solve the problem. Changing
to an oral contraceptive with a higher estrogen content, while potentially useful in min
imizing menstrual irregularity, should be done only if necessary since this may increase
the risk of thromboembolic disease.
Use of oral contraceptives in the event of a missed menstrual period:
1. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy
should be considered at the time of the first missed period and oral contraceptive
use should be discontinued if pregnancy is confirmed.
2. If the patient has adhered to the prescribed regimen and misses two consecutive
periods, pregnancy should be ruled out.
HOW SUPPLIED
ORTHO-NOVUM 7/7/7 Tablets are available in a DIALPAK Tablet Dispenser (NDC
0062-1781-15) containing 28 tablets, as follows: 7 white, round, flat-faced beveled
edged tablets imprinted with “Ortho 535” on both sides (0.5 mg norethindrone and
0.035 mg ethinyl estradiol), 7 light peach, round, flat-faced, beveled edged tablets im
printed with “Ortho 75” on both sides (0.75 mg norethindrone and 0.035 mg ethinyl estra
diol), 7 peach, round, flat-faced, beveled edged tablets imprinted with “Ortho 135” on
both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round,
flat-faced, beveled edged tablets imprinted “Ortho” on both sides containing inert in
gredients.
ORTHO-NOVUM 7/7/7 is available for clinic usage in a VERIDATE Tablet Dispenser
(unfilled) and VERIDATE Refills (NDC 0062-1781-20).
ORTHO-NOVUM 1/35 Tablets are available in a DIALPAK Tablet Dispenser (NDC 0062
1761-15) containing 28 tablets, as follows: 21 peach, round, flat-faced, beveled edged
tablets imprinted “Ortho 135” on both sides (1 mg norethindrone and 0.035 mg ethinyl
estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted “Ortho” on
both sides containing inert ingredients.
MODICON Tablets are available in a DIALPAK Tablet Dispenser (NDC 0062-1714
15) containing 28 tablets, as follows: 21 white, round, flat-faced, beveled edged
tablets imprinted “Ortho 535” on both sides (0.5 mg norethindrone and 0.035 mg
ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted
“Ortho” on both sides containing inert ingredients.
MODICON is available for clinic usage in a VERIDATE Tablet Dispenser (unfilled) and
VERIDATE Refills (NDC 0062-1714-20).
Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F).
REFERENCES
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MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use
of oral contraceptives: possible modifying effect of formulation and age at use. Lancet
1983; 2:926-929. 38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives
and breast cancer: A national study. Br Med J 1986; 293:723-725. 39. Miller DR,
Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk
in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863-868. 40. Olsson
H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast can
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K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast
cancer: Results of another case-control study. Br J Cancer 1987; 56:653-660. 42.
Huggins GR, Zucker PF. Oral contraceptives and neoplasia: 1987 update. Fertil Steril
1987; 47:733-761. 43. McPherson K, Drife JO. The pill and breast cancer: why the un
certainty? Br Med J 1986; 293:709-710. 44. Shapiro S. Oral contraceptives – time to
take stock. N Engl J Med 1987; 315:450-451. 45. Ory H, Naib Z, Conger SB, Hatcher
RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carci
noma in situ. Am J Obstet Gynecol 1976; 124:573-577. 46. Vessey MP, Lawless M,
McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible
adverse effect of the pill. Lancet 1983; 2:930. 47. Brinton LA, Huggins GR, Lehman HF,
Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contra
ceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339-344. 48. WHO
Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer
and combined oral contraceptives. Br Med J 1985; 290:961-965. 49. Rooks JB, Ory
HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepato
cellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648. 50. Bein
NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors sec
ondary to oral contraceptives. Br J Surg 1977; 64:433-435. 51. Klatskin G. Hepatic tu
mors: possible relationship to use of oral contraceptives. Gastroenterology 1977;
73:386-394. 52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC.
Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437-440. 53.
Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular car
cinoma. Br Med J 1986; 292:1355-1357. 54. Forman D, Vincent TJ, Doll R. Cancer of
the liver and oral contraceptives. Br Med J 1986; 292:1357-1361. 55. Harlap S, Eldor
J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452. 56.
Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed
in a national malformation register. Am J Obstet Gynecol 1981; 140:521-524. 57. Janerich
DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980;
112:73-79. 58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R.
Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239.
59. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other
drug exposures of children with congenital heart disease. Am J Epidemiol 1979;
109:433-439. 60. Boston Collaborative Drug Surveillance Program: Oral contracep
tives and venous thromboembolic disease, surgically confirmed gallbladder disease,
and breast tumors. Lancet 1973; 1:1399-1404. 61. Royal College of General Practitioners:
Oral contraceptives and health. New York, Pittman 1974. 62. Layde PM, Vessey MP,
Yeates D. Risk of gallbladder disease: a cohort study of young women attending fam
ily planning clinics. J Epidemiol Community Health 1982; 36:274-278. 63. Rome Group
for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone
disease in an Italian adult female population. Am J Epidemiol 1984; 119:796-805. 64.
Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral con
traceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986;
39:335-341. 65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R,
Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive
formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049. 66.
Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In:
Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P. eds. New York,
Raven Press, 1983; pp. 395-410. 67. Perlman JA, Roussell-Briefel RG, Ezzati TM,
Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progesto
gens. J Chronic Dis 1985; 38:857-864. 68. Royal College of General Practitioners’ Oral
Contraception Study: Effect on hypertension and benign breast disease of progesto
gen component in combined oral contraceptives. Lancet 1977; 1:624. 69. Fisch IR,
Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503. 70. Laragh
AJ. Oral contraceptive induced hypertension – nine years later. Am J Obstet Gynecol
1976; 126:141-147. 71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence
of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology
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1977; pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological
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Cancer and Steroid Hormone Study of the Centers for Disease Control and the National
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ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA
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HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann
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Evaluating the health risks and benefits of birth control methods. New York, The Alan
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Breast cancer and the pill – A further report from the Royal College of General Practitioners’
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Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in
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contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-
controlled trial. Epilepsia 2007;48(3):484-489.
BRIEF SUMMARY PATIENT PACKAGE INSERT
Oral contraceptives, also known as “birth control pills” or “the pill,” are taken to prevent
pregnancy and when taken correctly without missing any pills, have a failure rate of
approximately 1% per year. The typical failure rate is approximately 5% per year when
women who miss pills are included. For most women oral contraceptives are also free
of serious or unpleasant side effects. However, forgetting to take pills considerably in
creases the chances of pregnancy.
For the majority of women, oral contraceptives can be taken safely. But there are some
women who are at high risk of developing certain serious diseases that can be fatal or
may cause temporary or permanent disability. The risks associated with taking oral
contraceptives increase significantly if you:
• smoke
• have high blood pressure, diabetes, high cholesterol
• have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer
of the breast or sex organs, jaundice or malignant or benign liver tumors.
Although cardiovascular disease risks may be increased with oral contraceptive use
after age 40 in healthy, non-smoking women (even with the newer low-dose formula
tions), there are also greater potential health risks associated with pregnancy in older
women.
You should not take the pill if you suspect you are pregnant or have unexplained
vaginal bleeding.
Cigarette smoking increases the risk of serious cardiovascular side
effects from oral contraceptive use. This risk increases with age and with
heavy smoking (15 or more cigarettes per day) and is quite marked in
women over 35 years of age. Women who use oral contraceptives are
strongly advised not to smoke.
Most side effects of the pill are not serious. The most common such effects are nausea,
vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and
difficulty wearing contact lenses. These side effects, especially nausea and vomiting,
may subside within the first three months of use.
The serious side effects of the pill occur very infrequently, especially if you are in
good health and are young. However, you should know that the following medical
conditions have been associated with or made worse by the pill:
1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism),
stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood
vessels in the heart (heart attack or angina pectoris) or other organs of the
body. As mentioned above, smoking increases the risk of heart attacks and
strokes and subsequent serious medical consequences.
2. In rare cases, oral contraceptives can cause benign but dangerous liver
tumors. These benign liver tumors can rupture and cause fatal internal bleed
ing. In addition, some studies report an increased risk of developing liver
cancer. However, liver cancers are rare.
3. High blood pressure, although blood pressure usually returns to normal
when the pill is stopped.
The symptoms associated with these serious side effects are discussed
in the detailed leaflet given to you with your supply of pills. Notify your
healthcare professional if you notice any unusual physical disturbances
while taking the pill. In addition, drugs such as rifampin, as well as some
anticonvulsants and some antibiotics may decrease oral contraceptive
effectiveness.
Oral contraceptives may interact with lamotrigine (LAMICTAL®), an anti
convulsant used for epilepsy. This may increase the risk of seizures so your
barcode
healthcare professional may need to adjust the dose of lamotrigine.
Various studies give conflicting reports on the relationship between breast
cancer and oral contraceptive use. Oral contraceptive use may slightly increase your
chance of having breast cancer diagnosed, particularly after using hormonal contra
ceptives at a younger age. After you stop using hormonal contraceptives, the chances
of having breast cancer diagnosed begin to go back down. You should have regular
breast examinations by a healthcare professional and examine your own breasts
monthly. Tell your healthcare professional if you have a family history of breast cancer
or if you have had breast nodules or an abnormal mammogram. Women who currently
have or have had breast cancer should not use oral contraceptives because breast
cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in women
who use oral contraceptives. However, this finding may be related to factors other than
the use of oral contraceptives. There is insufficient evidence to rule out the possibility
that the pill may cause such cancers.
Taking the combination pill provides some important non-contraceptive benefits. These
include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic
infections, and fewer cancers of the ovary and the lining of the uterus.
Be sure to discuss any medical condition you may have with your healthcare pro
fessional. Your healthcare professional will take a medical and family history before
prescribing oral contraceptives and will examine you. The physical examination may
be delayed to another time if you request it and the healthcare professional believes
that it is a good medical practice to postpone it. You should be reexamined at least
once a year while taking oral contraceptives. Your pharmacist should have given you
the detailed patient information labeling which gives you further information which you
should read and discuss with your healthcare professional.
This product (like all oral contraceptives) is intended to prevent pregnancy. It does
not protect against transmission of HIV (AIDS) and other sexually transmitted
diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B,
and syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE
SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO
THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your
stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go
away, check with your healthcare professional.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when
you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick
to your stomach.
5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, in
cluding some antibiotics, your pills may not work as well. Use a back-up method (such
as condoms or spermicide) until you check with your healthcare professional.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your health
care professional about how to make pill-taking easier or about using another method
of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN
THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK.
The pill pack has 21 “active” pills (with hormones) to take for 3 weeks. This is followed
by 1 week of green “reminder” pills (without hormones).
ORTHO-NOVUM 7/7/7: There are 7 white “active” pills, 7 light peach “active” pills, 7
peach “active” pills and 7 green “reminder” pills.
ORTHO-NOVUM 1/35: There are 21 peach “active” pills and 7 green “reminder” pills.
MODICON: There are 21 white “active” pills and 7 green “reminder” pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a
back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM
7/7/7, ORTHO-NOVUM 1/35, and MODICON are available in the DIALPAK® Tablet
Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with
your healthcare professional which is the best day for you. Pick a time of day which
will be easy to remember.
SUNDAY START:
ORTHO-NOVUM 7/7/7: Take the first white “active” pill of the first pack on the Sunday
after your period starts, even if you are still bleeding. If your period begins on Sunday,
start the pack the same day.
ORTHO-NOVUM 1/35: Take the first peach “active” pill of the first pack on the Sunday
after your period starts, even if you are still bleeding. If your period begins on Sunday,
start the pack the same day.
MODICON: Take the first white “active” pill of the first pack on the Sunday after your
period starts, even if you are still bleeding. If your period begins on Sunday, start the
pack the same day.
Use another method of birth control such as condoms or spermicide as a back-up
method if you have sex anytime from the Sunday you start your first pack until the next
Sunday (7 days).
DAY 1 START:
ORTHO-NOVUM 7/7/7: Take the first white “active” pill of the first pack during the first
24 hours of your period.
ORTHO-NOVUM 1/35: Take the first peach “active” pill of the first pack during the first
24 hours of your period.
MODICON: Take the first white “active” pill of the first pack during the first 24 hours
of your period.
You will not need to use a back-up method of birth control, since you are starting the
pill at the beginning of your period.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel
sick to your stomach (nausea). Do not skip pills even if you do not have sex very often.
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last green “reminder” pill. Do not wait any
days between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO-NOVUM 7/7/7:
If you MISS 1 white, light peach, or peach “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means
you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light peach “active” pills in a row in WEEK 1 OR WEEK 2 of
your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 2 peach “active” pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE white, light peach, or peach “active” pills in a row (during
the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
ORTHO-NOVUM 1/35:
If you MISS 1 peach “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means
you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 peach “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 2 peach “active” pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE peach “active” pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
MODICON:
If you MISS 1 white “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means
you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 2 white “active” pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OTHER INFORMATION
Your healthcare professional will take a medical and family history before prescribing
oral contraceptives and will examine you. The physical examination may be delayed
to another time if you request it and the healthcare professional believes that it is a
good medical practice to postpone it. You should be reexamined at least once a
year. Be sure to inform your healthcare professional if there is a family history of any
of the conditions listed previously in this leaflet. Be sure to keep all appointments with
your healthcare professional, because this is a time to determine if there are early signs
of side effects of oral contraceptive use.
Do not use the drug for any condition other than the one for which it was prescribed.
This drug has been prescribed specifically for you; do not give it to others who may
want birth control pills.
HEALTH BENEFITS FROM ORAL CONTRACEPTIVES
In addition to preventing pregnancy, use of combination oral contraceptives may provide
certain benefits. They are:
• menstrual cycles may become more regular
• blood flow during menstruation may be lighter and less iron may be lost. Therefore,
anemia due to iron deficiency is less likely to occur.
• pain or other symptoms during menstruation may be encountered less frequently
• ectopic (tubal) pregnancy may occur less frequently
• noncancerous cysts or lumps in the breast may occur less frequently
• acute pelvic inflammatory disease may occur less frequently
• oral contraceptive use may provide some protection against developing two forms
of cancer: cancer of the ovaries and cancer of the lining of the uterus.
If you want more information about birth control pills, ask your healthcare professional.
They have a more technical leaflet called the Professional Labeling, which you may
wish to read. The professional labeling is also published in a book entitled Physicians’
Desk Reference, available in many book stores and public libraries.
If you MISS 3 OR MORE white “active” pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
A REMINDER
If you forget any of the 7 green “reminder” pills in Week 4: THROW AWAY the pills you
missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-
up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU
HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE “ACTIVE” PILL EACH DAY until you can reach your healthcare
professional.
INSTRUCTIONS FOR USE
DIALPAK® Tablet Dispenser
1. The DIALPAK comes to you set up for Sunday Start. If your physician has instructed
you to start pill-taking on the first SUNDAY after your menstrual period has begun, see
directions in Number 3.
2. If you are to start pill-taking on a day other than SUNDAY, the enclosed calendar
label has been provided and will be placed over the calendar printed on the plastic in
the center of the DIALPAK. To put label in place, identify your correct starting day, lo-
cate that day on the label, line that day up with the pill to which the word START and
the black Day Arrow are pointing, remove the label from the backing and press the
label over the printed calendar on the center plastic.
3. When the compact is open with the cover at top, the pills should be arranged as
they are in the picture. If not, turn the ribbed outer ring until the pills are positioned cor-
rectly.
ORTHO-NOVUM 7/7/7: There are 7 white “active” pills, 7 light peach “active” pills, 7
peach “active” pills and 7 green “reminder” pills.
ORTHO-NOVUM 1/35: There are 21 peach “active” pills and 7 green “reminder” pills.
MODICON: There are 21 white “active” pills and 7 green “reminder” pills.
4. The first pill you will take is indicated by START and lines up with the black Day
Arrow in the center of the DIALPAK. If not, see the directions in Number 3.
5. Push down on the first pill with your thumb or forefinger. The pill will come out through
a hole in the back of the package.
6. The next day, turn the DIAL to the right using the ribbed outer ring to the next pill
and your second pill is ready to be taken.
7. After you have taken all 21 pills, take one green “reminder” pill daily for 7 days.
During this time your period should begin.
8. After you have taken all the pills, start a new pack of pills even if your period is not
yet over.
HOW TO INSERT REFILL (ORTHO-NOVUM 7/7/7 ONLY)
1. Lift the empty refill out of the DIALPAK. Insert the new refill by placing the black tab
on refill into the opening in the ribbed outer ring of the DIALPAK (see drawing).
2. Press the refill down so that it fits firmly under the nibs. The DIAL should be turned
by the ribbed outer ring so that the tablets are again arranged as in the drawing. The
first white tablet will be directly over the black DAY ARROW.
DETAILED PATIENT LABELING
PLEASE NOTE: This labeling is revised from time to time as important new medical
information becomes available. Therefore, please review this labeling carefully.
The following oral contraceptive products contain a combination of an estrogen and
progestogen, the two kinds of female hormones:
ORTHO-NOVUM® 7/7/7
Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each
light peach tablet contains 0.75 mg norethindrone and 0.035 mg ethinyl estradiol. Each
peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each green
tablet contains inert ingredients.
ORTHO-NOVUM® 1/35
Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each
green tablet contains inert ingredients.
MODICON®
Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each
green tablet contains inert ingredients.
INTRODUCTION
Any woman who considers using oral contraceptives (the birth control pill or the pill)
should understand the benefits and risks of using this form of birth control. This patient
labeling will give you much of the information you will need to make this decision and
will also help you determine if you are at risk of developing any of the serious side
effects of the pill. It will tell you how to use the pill properly so that it will be as effective
as possible. However, this labeling is not a replacement for a careful discussion be-
tween you and your healthcare professional. You should discuss the information pro-
vided in this labeling with him or her, both when you first start taking the pill and during
your revisits. You should also follow your healthcare professional’s advice with regard
to regular check-ups while you are on the pill.
EFFECTIVENESS OF ORAL CONTRACEPTIVES
Oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy
and are more effective than other non-surgical methods of birth control. When they are
taken correctly without missing any pills, the chance of becoming pregnant is
approximately 1% (1 pregnancy per 100 women per year of use). Typical failure rates
are approximately 5% per year including women who do not always take the pills exactly
as directed. The chance of becoming pregnant increases with each missed pill during
a menstrual cycle.
In comparison, typical failure rates for other methods of birth control during the first
year of use are as follows:
Implant: <1%
Male sterilization: <1%
Injection: <1%
Cervical Cap with spermicides: 20 to 40%
IUD: 1 to 2%
Condom alone (male): 14%
Diaphragm with spermicides: 20%
Condom alone (female): 21%
Spermicides alone: 26%
Periodic abstinence: 25%
Vaginal sponge: 20 to 40%
Withdrawal: 19%
Female sterilization: <1%
No methods: 85%
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Some women should not use the pill. For example, you should not take the pill if you
have any of the following conditions:
• A history of heart attack or stroke
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
• A history of blood clots in the deep veins of your legs
• Chest pain (angina pectoris)
• Known or suspected breast cancer or cancer of the lining of the uterus, cervix
or vagina
• Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare
professional)
• Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or dur-
ing previous use of the pill
• Liver tumor (benign or cancerous)
• Known or suspected pregnancy
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• If you plan to have surgery with prolonged bedrest
• Hypersensitivity to any component of this product.
Tell your healthcare professional if you have ever had any of these conditions. Your
healthcare professional can recommend a safer method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare professional if you have or have had:
• Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or
mammogram
• Diabetes
• Elevated cholesterol or triglycerides
• High blood pressure
• Migraine or other headaches or epilepsy
• Mental depression
• Gallbladder, liver, heart or kidney disease
• History of scanty or irregular menstrual periods
Women with any of these conditions should be checked often by their healthcare
professional if they choose to use oral contraceptives.
Also, be sure to inform your healthcare professional if you smoke or are on any
medications.
RISKS OF TAKING ORAL CONTRACEPTIVES
1. Risk of developing blood clots
Blood clots and blockage of blood vessels are one of the most serious side effects of
taking oral contraceptives and can cause death or serious disability. In particular, a clot
in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause
a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the
blood vessels of the eye and may cause blindness, double vision, or impaired vision.
If you take oral contraceptives and need elective surgery, need to stay in bed for a pro-
longed illness or injury or have recently delivered a baby, you may be at risk of devel-
oping blood clots. You should consult your healthcare professional about stopping oral
contraceptives three to four weeks before surgery and not taking oral contraceptives
for two weeks after surgery or during bed rest. You should also not take oral contra-
ceptives soon after delivery of a baby. It is advisable to wait for at least four weeks
after delivery if you are not breast feeding or four weeks after a second trimester abor-
tion. If you are breast feeding, you should wait until you have weaned your child be-
fore using the pill. (See also the section on Breast Feeding in General Precautions.)
The risk of circulatory disease in oral contraceptive users may be higher in users of
high dose pills and may be greater with longer duration of oral contraceptive use. In
addition, some of these increased risks may continue for a number of years after
stopping oral contraceptives. The risk of abnormal blood clotting increases with age
in both users and nonusers of oral contraceptives, but the increased risk from the oral
contraceptive appears to be present at all ages. For women aged 20 to 44, it is esti-
mated that about 1 in 2,000 using oral contraceptives will be hospitalized each year
because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000
would be hospitalized each year. For oral contraceptive users in general, it has been
estimated that in women between the ages of 15 and 34 the risk of death due to a cir-
culatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about
1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in
2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers.
2. Heart attacks and strokes
Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture
of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood
vessels in the heart). Any of these conditions can cause death or serious disability.
Smoking greatly increases the possibility of suffering heart attacks and strokes.
Furthermore, smoking and the use of oral contraceptives greatly increase the chances
of developing and dying of heart disease.
3. Gallbladder disease
Oral contraceptive users probably have a greater risk than nonusers of having gallbladder
disease, although this risk may be related to pills containing high doses of estrogens.
4. Liver tumors
In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These
benign liver tumors can rupture and cause fatal internal bleeding. In addition, some
studies report an increased risk of developing liver cancer. However, liver cancers are
rare.
5. Cancer of the reproductive organs and breasts
Various studies give conflicting reports on the relationship between breast cancer and
oral contraceptive use. Oral contraceptive use may slightly increase your chance of
having breast cancer diagnosed, particularly after using hormonal contraceptives at a
younger age. After you stop using hormonal contraceptives, the chances of having
breast cancer diagnosed begin to go back down. You should have regular breast ex-
aminations by a healthcare professional and examine your own breasts monthly. Tell
your healthcare professional if you have a family history of breast cancer or if you have
had breast nodules or an abnormal mammogram. Women who currently have or have
had breast cancer should not use oral contraceptives because breast cancer is usu-
ally a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in women
who use oral contraceptives. However, this finding may be related to factors other than
the use of oral contraceptives. There is insufficient evidence to rule out the possibility
that the pill may cause such cancers.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR
PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing
certain diseases which may lead to disability or death. An estimate of the number of
deaths associated with different methods of birth control and pregnancy has been cal-
culated and is shown in the following table.
ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS
ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN,
BY FERTILITY CONTROL METHOD ACCORDING TO AGE
Method of control
15-19
20-24
25-29
30-34
35-39
40-44
and outcome
No fertility
7.0
7.4
9.1
14.8
25.7
28.2
control methods*
Oral contraceptives
0.3
0.5
0.9
1.9
13.8
31.6
non-smoker**
Oral contraceptives
2.2
3.4
6.6
13.5
51.1
117.2
smoker**
IUD**
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/
1.9
1.2
1.2
1.3
2.2
2.8
spermicide*
Periodic
2.5
1.6
1.6
1.7
2.9
3.6
abstinence*
*Deaths are birth-related
**Deaths are method-related
In the above table, the risk of death from any birth control method is less than the risk
of childbirth, except for oral contraceptive users over the age of 35 who smoke and
pill users over the age of 40 even if they do not smoke. It can be seen in the table that
for women aged 15 to 39, the risk of death was highest with pregnancy (7-26 deaths
per 100,000 women, depending on age). Among pill users who do not smoke, the risk
of death was always lower than that associated with pregnancy for any age group, al-
though over the age of 40, the risk increases to 32 deaths per 100,000 women, com-
pared to 28 associated with pregnancy at that age. However, for pill users who smoke
and are over the age of 35, the estimated number of deaths exceeds those for other
methods of birth control. If a woman is over the age of 40 and smokes, her estimated
risk of death is four times higher (117/100,000 women) than the estimated risk asso-
ciated with pregnancy (28/100,000 women) in that age group.
The suggestion that women over 40 who do not smoke should not take oral contra-
ceptives is based on information from older, higher-dose pills. An Advisory Committee
of the FDA discussed this issue in 1989 and recommended that the benefits of low-
dose oral contraceptive use by healthy, non-smoking women over 40 years of age may
outweigh the possible risks.
WARNING SIGNALS
If any of these adverse effects occur while you are taking oral contraceptives, call your
healthcare professional immediately:
• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a
possible clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain or heaviness in the chest (indicating a possible heart attack)
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision
or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast;
ask your healthcare professional to show you how to examine your breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver
tumor)
• Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly
indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fa-
tigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating
possible liver problems)
Cigarette smoking increases the risk of serious cardiovascular side
effects from oral contraceptive use. This risk increases with age and with
heavy smoking (15 or more cigarettes per day) and is quite marked in
women over 35 years of age. Women who use oral contraceptives are
strongly advised not to smoke.
*
SIDE EFFECTS OF ORAL CONTRACEPTIVES
1. Vaginal bleeding
Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular
bleeding may vary from slight staining between menstrual periods to breakthrough bleed
ing which is a flow much like a regular period. Irregular bleeding occurs most often
during the first few months of oral contraceptive use, but may also occur after you have
been taking the pill for some time. Such bleeding may be temporary and usually does
not indicate any serious problems. It is important to continue taking your pills on sched
ule. If the bleeding occurs in more than one cycle or lasts for more than a few days,
talk to your healthcare professional.
2. Contact lenses
If you wear contact lenses and notice a change in vision or an inability to wear your
lenses, contact your healthcare professional.
3. Fluid retention
Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or
ankles and may raise your blood pressure. If you experience fluid retention, contact
your healthcare professional.
4. Melasma
A spotty darkening of the skin is possible, particularly of the face, which may persist.
5. Other side effects
Other side effects may include nausea and vomiting, change in appetite, headache,
nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, and al
lergic reactions.
If any of these side effects bother you, call your healthcare professional.
GENERAL PRECAUTIONS
1. Missed periods and use of oral contraceptives before or during early pregnancy
There may be times when you may not menstruate regularly after you have completed
taking a cycle of pills. If you have taken your pills regularly and miss one menstrual pe
riod, continue taking your pills for the next cycle but be sure to inform your healthcare
professional before doing so. If you have not taken the pills daily as instructed and
missed a menstrual period, you may be pregnant. If you missed two consecutive
menstrual periods, you may be pregnant. Check with your healthcare professional
immediately to determine whether you are pregnant. Do not continue to take oral con
traceptives until you are sure you are not pregnant, but continue to use another method
of contraception.
There is no conclusive evidence that oral contraceptive use is associated with an
increase in birth defects, when taken inadvertently during early pregnancy. Previously,
a few studies had reported that oral contraceptives might be associated with birth de
fects, but these findings have not been seen in more recent studies. Nevertheless, oral
contraceptives should not be used during pregnancy. You should check with your health
care professional about risks to your unborn child of any medication taken during preg
nancy.
2. While breast feeding
If you are breast feeding, consult your healthcare professional before starting oral con
traceptives. Some of the drug will be passed on to the child in the milk. A few adverse
effects on the child have been reported, including yellowing of the skin (jaundice) and
breast enlargement. In addition, combination oral contraceptives may decrease the
amount and quality of your milk. If possible, do not use combination oral contracep
tives while breast feeding. You should use another method of contraception since breast
feeding provides only partial protection from becoming pregnant and this partial pro
tection decreases significantly as you breast feed for longer periods of time. You should
consider starting combination oral contraceptives only after you have weaned your
child completely.
3. Laboratory tests
If you are scheduled for any laboratory tests, tell your healthcare professional you
are taking birth control pills. Certain blood tests may be affected by birth control pills.
4. Drug interactions
Certain drugs may interact with birth control pills to make them less effective in
preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs
include rifampin, drugs used for epilepsy such as barbiturates (for example, pheno
barbital), topiramate (TOPAMAX®), carbamazepine (Tegretol® is one brand of this drug),
phenytoin (Dilantin® is one brand of this drug), phenylbutazone (Butazolidin® is one brand),
certain drugs used in the treatment of HIV or AIDS, and possibly certain antibiotics.
Medicine for pulmonary hypertension, such as bosentan (Tracleer®). Pregnancies and
breakthrough bleeding have been reported by users of combined hormonal contra
ceptives who also used some form of the herbal supplement St. John’s Wort. Hormonal
contraceptives may interact with lamotrigine (LAMICTAL®), an anticonvulsant used for
epilepsy. This may increase the risk of seizures so your healthcare professional may
need to adjust the dose of lamotrigine. You may need to use additional contraception
when you take other products which can make oral contraceptives less effective. Be
sure to tell your healthcare professional if you are taking or start taking any medications
while taking birth control pills.
5. Sexually transmitted diseases
This product (like all oral contraceptives) is intended to prevent pregnancy. It does
not protect against transmission of HIV (AIDS) and other sexually transmitted
diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B,
and syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE
SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO
THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your
stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go
away, check with your healthcare professional.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when
you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick
to your stomach.
5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, in
cluding some antibiotics, your pills may not work as well. Use a back-up method (such
as condoms or spermicide) until you check with your healthcare professional.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your health
care professional about how to make pill-taking easier or about using another method
of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN
THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK.
The pill pack has 21 “active” pills (with hormones) to take for 3 weeks. This is followed
by 1 week of green “reminder” pills (without hormones).
ORTHO-NOVUM 7/7/7: There are 7 white “active” pills, 7 light peach “active” pills, 7
peach “active” pills and 7 green “reminder” pills.
ORTHO-NOVUM 1/35: There are 21 peach “active” pills and 7 green “reminder” pills.
MODICON: There are 21 white “active” pills and 7 green “reminder” pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING
THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a
back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM
7/7/7, ORTHO-NOVUM 1/35, and MODICON are available in the DIALPAK® Tablet
Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with
your healthcare professional which is the best day for you. Pick a time of day which
will be easy to remember.
SUNDAY START:
ORTHO-NOVUM 7/7/7: Take the first white “active” pill of the first pack on the Sunday
after your period starts, even if you are still bleeding. If your period begins on Sunday,
start the pack the same day.
ORTHO-NOVUM 1/35: Take the first peach “active” pill of the first pack on the Sunday
after your period starts, even if you are still bleeding. If your period begins on Sunday,
start the pack the same day.
MODICON: Take the first white “active” pill of the first pack on the Sunday after your
period starts, even if you are still bleeding. If your period begins on Sunday, start the
pack the same day.
Use another method of birth control such as condoms or spermicide as a back-up
method if you have sex anytime from the Sunday you start your first pack until the next
Sunday (7 days).
DAY 1 START:
ORTHO-NOVUM 7/7/7: Take the first white “active” pill of the first pack during the first
24 hours of your period.
ORTHO-NOVUM 1/35: Take the first peach “active” pill of the first pack during the first
24 hours of your period.
MODICON: Take the first white “active” pill of the first pack during the first 24 hours
of your period.
You will not need to use a back-up method of birth control, since you are starting the
pill at the beginning of your period.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel
sick to your stomach (nausea).
Do not skip pills even if you do not have sex very often.
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last green “reminder” pill. Do not wait any
days between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO-NOVUM 7/7/7:
If you MISS 1 white, light peach, or peach “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means
you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light peach “active” pills in a row in WEEK 1 OR WEEK 2 of
your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 2 peach “active” pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE white, light peach, or peach “active” pills in a row (during
the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
ORTHO-NOVUM 1/35:
If you MISS 1 peach “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means
you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 peach “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 2 peach “active” pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE peach “active” pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
MODICON:
If you MISS 1 white “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means
you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 2 white “active” pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE white “active” pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss
your period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as condoms or spermicide) as a
back-up method for those 7 days.
A REMINDER
If you forget any of the 7 green “reminder” pills in Week 4: THROW AWAY the pills you
missed. Keep taking 1 pill each day until the pack is empty. You do not need a back
up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU
HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE “ACTIVE” PILL EACH DAY until you can reach your healthcare
professional.
PREGNANCY DUE TO PILL FAILURE
Combination Oral Contraceptives
The incidence of pill failure resulting in pregnancy is approximately one percent
(i.e., one pregnancy per 100 women per year) if taken every day as directed, but more
typical failure rates are 5%. If failure does occur, the risk to the fetus is minimal.
PREGNANCY AFTER STOPPING THE PILL
There may be some delay in becoming pregnant after you stop using oral contracep
tives, especially if you had irregular menstrual cycles before you used oral contraceptives.
It may be advisable to postpone conception until you begin menstruating regularly once
you have stopped taking the pill and desire pregnancy.
There does not appear to be any increase in birth defects in newborn babies when
pregnancy occurs soon after stopping the pill.
OVERDOSAGE
Serious ill effects have not been reported following ingestion of large doses of oral con
traceptives by young children. Overdosage may cause nausea and withdrawal bleed
ing in females. In case of overdosage, contact your healthcare professional
or pharmacist.
Mfd. for:
Ortho Women’s Health & Urology,
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Raritan, New Jersey 08869
Mfd. by:
Janssen Ortho, LLC
Manati, Puerto Rico 00674
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998
PRINTED IN U.S.A.
Revised September 2008
10159300 Ortho Women's Health and Urology logo
barcode
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:24.479160
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017735s107lbl.pdf', 'application_number': 17919, 'submission_type': 'SUPPL ', 'submission_number': 89}
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11,091
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company logo
TABLETS
CLINORIL®
(SULINDAC)
Cardiovascular Risk
•
NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients
with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
(See WARNINGS.)
•
CLINORIL is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
•
NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can
occur at any time during use and without warning symptoms. Elderly patients are at greater risk
for serious gastrointestinal events. (See WARNINGS.)
DESCRIPTION
Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-fluoro
2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid. It is not a salicylate, pyrazolone
or propionic acid derivative. Its empirical formula is C20H17FO3S, with a molecular weight of 356.42.
Sulindac, a yellow crystalline compound, is a weak organic acid practically insoluble in water below
pH 4.5, but very soluble as the sodium salt or in buffers of pH 6 or higher.
CLINORIL* (Sulindac) is available in 200 mg tablets for oral administration. Each tablet contains the
following inactive ingredients: cellulose, magnesium stearate, starch.
Following absorption, sulindac undergoes two major biotransformations ⎯ reversible reduction to the
sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Available evidence indicates that
the biological activity resides with the sulfide metabolite.
The structural formulas of sulindac and its metabolites are:
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1988, 2005 MERCK & CO., Inc.
All rights reserved
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac) structural formula
CLINICAL PHARMACOLOGY
Pharmacodynamics
CLINORIL is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic
and antipyretic activities in animal models. The mechanism of action, like that of other NSAIDs, is not
completely understood but may be related to prostaglandin synthetase inhibition.
Pharmacokinetics
Absorption
The extent of sulindac absorption from CLINORIL Tablets is similar as compared to sulindac solution.
There is no information regarding food effect on sulindac absorption. Antacids containing magnesium
hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL have been shown not to significantly
decrease the extent of sulindac absorption.
TABLE
1
PHARMACOKINETIC
PARAMETERS
NORMAL
ELDERLY
Tmax
Age 19-41 (n=24)
(200 mg tablet)
3.38 ± 2.30 S
4.88 ± 2.57 SP
4.96 ± 2.36 SF
(150 mg tablet)
3.90 ± 2.30 S
5.85 ±4.49 SP
6.15 ± 3.07 SF
Age 65-87 (n=12) 400 mg qd
2.54 ± 1.52 S
5.75 ± 2.81 SF
6.83 ± 4.19 SP
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
Renal Clearance
(200 mg tablet)
68.12 ± 27.56 mL/min S
36.58 ± 12.61 mL/min SP
(150 mg tablet)
74.39 ± 34.15 mL/min S
41.75 ± 13.72 mL/min SP
Mean effective Half life
(h)
7.8 S
16.4 SF
S = Sulindac
SF = Sulindac Sulfide
SP = Sulindac Sulfone
Distribution
Sulindac, and its sulfone and sulfide metabolites, are 93.1, 95.4, and 97.9% bound to plasma proteins,
predominantly to albumin. Plasma protein binding measured over a concentration range (0.5-2.0 μg/mL)
was constant. Following an oral, radiolabeled dose of sulindac in rats, concentrations of radiolabel in red
blood cells were about 10% of those in plasma. Sulindac penetrates the blood-brain and placental
barriers. Concentrations in brain did not exceed 4% of those in plasma. Plasma concentrations in the
placenta and in the fetus were less than 25% and 5% respectively, of systemic plasma concentrations.
Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not
known if sulindac is excreted in human milk.
Metabolism
Sulindac undergoes two major biotransformations of its sulfoxide moiety: oxidation to the inactive
sulfone and reduction to the pharmacologically active sulfide. The latter is readily reversible in animals
and in man. These metabolites are present as unchanged compounds in plasma and principally as
glucuronide conjugates in human urine and bile. A dihydroxydihydro analog has also been identified as a
minor metabolite in human urine.
With the twice-a-day dosage regimen, plasma concentrations of sulindac and its two metabolites
accumulate: mean concentration over a dosage interval at steady state relative to the first dose averages
1.5 and 2.5 times higher, respectively, for sulindac and its active sulfide metabolite.
Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the sulfide
metabolite in animals. Studies in man have also demonstrated that recirculation of the parent drug
sulindac and its sulfone metabolite is more extensive than that of the active sulfide metabolite. The active
sulfide metabolite accounts for less than six percent of the total intestinal exposure to sulindac and its
metabolites.
Biochemical as well as pharmacological evidence indicates that the activity of sulindac resides in its
sulfide metabolite. An in-vitro assay for inhibition of cyclooxygenase activity exhibited an EC50 of 0.02 μM
for sulindac sulfide. In-vivo models of inflammation indicate that activity is more highly correlated with
concentrations of the metabolite than with parent drug concentrations.
Elimination
Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated
sulfone metabolite accounting for the major portion. Less than 1% of the administered dose of sulindac
appears in the urine as the sulfide metabolite. Approximately 25% is found in the feces, primarily as the
sulfone and sulfide metabolites.
The mean effective half-life (T1/2) is 7.8 and 16.4 hours, respectively, for sulindac and its active sulfide
metabolite.
Because CLINORIL is excreted in the urine primarily as biologically inactive forms, it may possibly
affect renal function to a lesser extent than other non-steroidal anti-inflammatory drugs; however, renal
adverse experiences have been reported with CLINORIL (see ADVERSE REACTIONS).
In a study of patients with chronic glomerular disease treated with therapeutic doses of CLINORIL, no
effect was demonstrated on renal blood flow, glomerular filtration rate, or urinary excretion of
prostaglandin E2 and the primary metabolite of prostacyclin, 6-keto-PGF1α. However, in other studies in
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
healthy volunteers and patients with liver disease, CLINORIL was found to blunt the renal responses to
intravenous furosemide, i.e., the diuresis, natriuresis, increments in plasma renin activity and urinary
excretion of prostaglandins. These observations may represent a differentiation of the effects of
CLINORIL on renal functions based on differences in pathogenesis of the renal prostaglandin
dependence associated with differing dose-response relationships of different NSAIDs to the various
renal functions influenced by prostaglandins (see PRECAUTIONS).
In healthy men, the average fecal blood loss, measured over a two-week period during administration
of 400 mg per day of CLINORIL, was similar to that for placebo, and was statistically significantly less
than that resulting from 4800 mg per day of aspirin.
Special Populations
Pediatric
The pharmacokinetics of sulindac have not been investigated in pediatric patients.
Race
Pharmacokinetic differences due to race have not been identified.
Hepatic Insufficiency
Patients with acute and chronic hepatic disease may require reduced doses of CLINORIL compared
to patients with normal hepatic function since hepatic metabolism is an important elimination pathway.
Following a single dose, plasma concentrations of the active sulfide metabolite have been reported to
be higher in patients with alcoholic liver disease compared to healthy normal subjects.
Renal Insufficiency
Sulindac pharmacokinetics have been investigated in patients with renal insufficiency. The disposition
of sulindac was studied in end-stage renal disease patients requiring hemodialysis. Plasma
concentrations of sulindac and its sulfone metabolite were comparable to those of normal healthy
volunteers whereas concentrations of the active sulfide metabolite were significantly reduced. Plasma
protein binding was reduced and the AUC of the unbound sulfide metabolite was about half that in
healthy subjects.
Sulindac and its metabolites are not significantly removed from the blood in patients undergoing
hemodialysis.
Since CLINORIL is eliminated primarily by the kidneys, patients with significantly impaired renal
function should be closely monitored.
A lower daily dosage should be anticipated to avoid excessive drug accumulation.
In controlled clinical studies CLINORIL was evaluated in the following five conditions:
1. Osteoarthritis
In patients with osteoarthritis of the hip and knee, the anti-inflammatory and analgesic activity of
CLINORIL was demonstrated by clinical measurements that included: assessments by both patient and
investigator of overall response; decrease in disease activity as assessed by both patient and
investigator; improvement in ARA Functional Class; relief of night pain; improvement in overall evaluation
of pain, including pain on weight bearing and pain on active and passive motion; improvement in joint
mobility, range of motion, and functional activities; decreased swelling and tenderness; and decreased
duration of stiffness following prolonged inactivity.
In clinical studies in which dosages were adjusted according to patient needs, CLINORIL 200 to
400 mg daily was shown to be comparable in effectiveness to aspirin 2400 to 4800 mg daily. CLINORIL
was generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of
milder gastrointestinal reactions, and of tinnitus than did patients on aspirin. (See ADVERSE
REACTIONS.)
2. Rheumatoid arthritis
In patients with rheumatoid arthritis, the anti-inflammatory and analgesic activity of CLINORIL was
demonstrated by clinical measurements that included: assessments by both patient and investigator of
overall response; decrease in disease activity as assessed by both patient and investigator; reduction in
overall joint pain; reduction in duration and severity of morning stiffness; reduction in day and night pain;
decrease in time required to walk 50 feet; decrease in general pain as measured on a visual analog
scale; improvement in the Ritchie articular index; decrease in proximal interphalangeal joint size;
improvement in ARA Functional Class; increase in grip strength; reduction in painful joint count and
score; reduction in swollen joint count and score; and increased flexion and extension of the wrist.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
In clinical studies in which dosages were adjusted according to patient needs, CLINORIL 300 to
400 mg daily was shown to be comparable in effectiveness to aspirin 3600 to 4800 mg daily. CLINORIL
was generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of
milder gastrointestinal reactions, and of tinnitus than did patients on aspirin. (See ADVERSE
REACTIONS.)
In patients with rheumatoid arthritis, CLINORIL may be used in combination with gold salts at usual
dosage levels. In clinical studies, CLINORIL added to the regimen of gold salts usually resulted in
additional symptomatic relief but did not alter the course of the underlying disease.
3. Ankylosing spondylitis
In patients with ankylosing spondylitis, the anti-inflammatory and analgesic activity of CLINORIL was
demonstrated by clinical measurements that included: assessments by both patient and investigator of
overall response; decrease in disease activity as assessed by both patient and investigator; improvement
in ARA Functional Class; improvement in patient and investigator evaluation of spinal pain, tenderness
and/or spasm; reduction in the duration of morning stiffness; increase in the time to onset of fatigue; relief
of night pain; increase in chest expansion; and increase in spinal mobility evaluated by fingers-to-floor
distance, occiput to wall distance, the Schober Test, and the Wright Modification of the Schober Test. In a
clinical study in which dosages were adjusted according to patient need, CLINORIL 200 to 400 mg daily
was as effective as indomethacin 75 to 150 mg daily. In a second study, CLINORIL 300 to 400 mg daily
was comparable in effectiveness to phenylbutazone 400 to 600 mg daily. CLINORIL was better tolerated
than phenylbutazone. (See ADVERSE REACTIONS.)
4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
In patients with acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), the anti
inflammatory and analgesic activity of CLINORIL was demonstrated by clinical measurements that
included: assessments by both patient and investigator of overall response; relief of night pain,
spontaneous pain, and pain on active motion; decrease in local tenderness; and improvement in range of
motion measured by abduction, and internal and external rotation. In clinical studies in acute painful
shoulder, CLINORIL 300 to 400 mg daily and oxyphenbutazone 400 to 600 mg daily were shown to be
equally effective and well tolerated.
5. Acute gouty arthritis
In patients with acute gouty arthritis, the anti-inflammatory and analgesic activity of CLINORIL was
demonstrated by clinical measurements that included: assessments by both the patient and investigator
of overall response; relief of weight-bearing pain; relief of pain at rest and on active and passive motion;
decrease in tenderness; reduction in warmth and swelling; increase in range of motion; and improvement
in ability to function. In clinical studies, CLINORIL at 400 mg daily and phenylbutazone at 600 mg daily
were shown to be equally effective. In these short-term studies in which reduction of dosage was
permitted according to response, both drugs were equally well tolerated.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of CLINORIL and other treatment options before
deciding to use CLINORIL. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
CLINORIL is indicated for acute or long-term use in the relief of signs and symptoms of the following:
1. Osteoarthritis
2. Rheumatoid arthritis**
3. Ankylosing spondylitis
4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
5. Acute gouty arthritis
**The safety and effectiveness of CLINORIL have not been established in rheumatoid arthritis patients who are designated in the American
Rheumatism Association classification as Functional Class IV (incapacitated, largely or wholly bedridden, or confined to wheelchair; little or no self-
care).
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
CONTRAINDICATIONS
CLINORIL is contraindicated in patients with known hypersensitivity to sulindac or the excipients (see
DESCRIPTION).
CLINORIL should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions
to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactic/Anaphylactoid
Reactions, and PRECAUTIONS – Preexisting Asthma).
CLINORIL is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.
Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the
potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should
be used for the shortest duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV symptoms. Patients should be informed
about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10
14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see
CONTRAINDICATIONS).
Hypertension
NSAIDs, including CLINORIL, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs,
including CLINORIL, should be used with caution in patients with hypertension. Blood pressure (BP)
should be monitored closely during the initiation of NSAID treatment and throughout the course of
therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. CLINORIL should be
used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including CLINORIL, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused
by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients
treated for one year. These trends continue with longer duration of use, increasing the likelihood of
developing a serious GI event at some time during the course of therapy. However, even short-term
therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared
to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients
treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of
NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken
in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate
additional evaluation and treatment if a serious GI adverse event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate
therapies that do not involve NSAIDs should be considered.
Hepatic Effects
In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent
with those of cholestatic hepatitis (see WARNINGS, Hypersensitivity). As with other non-steroidal anti
inflammatory drugs, borderline elevations of one or more liver tests without any other signs and
symptoms may occur in up to 15% of patients taking NSAIDs including CLINORIL. These laboratory
abnormalities may progress, may remain essentially unchanged, or may be transient with continued
therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3
times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in
less than 1% of patients. Notable elevations of ALT or AST (approximately three or more times the upper
limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In
addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver
necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction
while on therapy with CLINORIL. Although such reactions as described above are rare, if abnormal liver
tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.), CLINORIL should be discontinued.
In clinical trials with CLINORIL, the use of doses of 600 mg/day has been associated with an
increased incidence of mild liver test abnormalities (see DOSAGE AND ADMINISTRATION for maximum
dosage recommendation).
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory
drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood
flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are
those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE
inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually
followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of CLINORIL in patients
with advanced renal disease. Therefore, treatment with CLINORIL is not recommended in these patients
with advanced renal disease. If CLINORIL therapy must be initiated, close monitoring of the patient’s
renal function is advisable.
Anaphylactic/Anaphylactoid Reactions
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior
exposure to CLINORIL. CLINORIL should not be given to patients with the aspirin triad. This symptom
complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactic/anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including CLINORIL, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs and symptoms of
serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
Hypersensitivity
Rarely, fever and other evidence of hypersensitivity (see ADVERSE REACTIONS) including
abnormalities in one or more liver function tests and severe skin reactions have occurred during therapy
with CLINORIL. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without
fever, may occur usually within the first one to three months of therapy. Determinations of liver function
should be considered whenever a patient on therapy with CLINORIL develops unexplained fever, rash or
other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of
hypersensitivity occurs, therapy with CLINORIL should be discontinued. The elevated temperature and
abnormalities in liver function caused by CLINORIL characteristically have reverted to normal after
discontinuation of therapy. Administration of CLINORIL should not be reinstituted in such patients.
Pregnancy
In late pregnancy, as with other NSAIDs, CLINORIL should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
CLINORIL cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of CLINORIL in reducing fever and inflammation may diminish the utility
of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including CLINORIL. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including CLINORIL, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving CLINORIL who may be adversely affected by alterations in platelet function, such as
those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has
been reported in such aspirin-sensitive patients, CLINORIL should not be administered to patients with
this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Renal Calculi
Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in
association with other calculus components. CLINORIL should be used with caution in patients with a
history of renal lithiasis, and they should be kept well hydrated while receiving CLINORIL.
Pancreatitis
Pancreatitis has been reported in patients receiving CLINORIL (see ADVERSE REACTIONS). Should
pancreatitis be suspected, the drug should be discontinued and not restarted, supportive medical therapy
instituted, and the patient monitored closely with appropriate laboratory studies (e.g., serum and urine
amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase, etc.). A search
for other causes of pancreatitis as well as those conditions which mimic pancreatitis should be
conducted.
Ocular Effects
Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is
recommended that patients who develop eye complaints during treatment with CLINORIL have
ophthalmologic studies.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
Hepatic Insufficiency
In patients with poor liver function, delayed, elevated and prolonged circulating levels of the sulfide
and sulfone metabolites may occur. Such patients should be monitored closely; a reduction of daily
dosage may be required.
SLE and Mixed Connective Tissue Disease
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, there may
be an increased risk of aseptic meningitis (see ADVERSE REACTIONS).
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged
to read the NSAID Medication Guide that accompanies each prescription dispensed.
1. CLINORIL, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may
result in hospitalization and even death. Although serious CV events can occur without warning
symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath,
weakness, slurring of speech, and should ask for medical advice when observing any indicative sign
or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS,
CARDIOVASCULAR EFFECTS).
2. CLINORIL, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as
ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract
ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs
and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any
indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal
Effects - Risk of Ulceration, Bleeding, and Perforation).
3. CLINORIL, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis,
SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions
may occur without warning, patients should be alert for the signs and symptoms of skin rash and
blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice
when observing any indicative signs or symptoms. Patients should be advised to stop the drug
immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty
breathing, swelling of the face or throat). If these occur, patients should be instructed to seek
immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, CLINORIL should be avoided because it may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, CLINORIL should be discontinued.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
Drug Interactions
ACE-Inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and
angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs
concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal
function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy)
who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of an NSAID and
an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function,
including possible acute renal failure, which is usually reversible. Therefore, the combination should be
administered with caution in patients with compromised renal function.
Acetaminophen
Acetaminophen had no effect on the plasma levels of sulindac or its sulfide metabolite.
Aspirin
The concomitant administration of aspirin with sulindac significantly depressed the plasma levels of
the active sulfide metabolite. A double-blind study compared the safety and efficacy of CLINORIL 300 or
400 mg daily given alone or with aspirin 2.4 g/day for the treatment of osteoarthritis. The addition of
aspirin did not alter the types of clinical or laboratory adverse experiences for CLINORIL; however, the
combination showed an increase in the incidence of gastrointestinal adverse experiences. Since the
addition of aspirin did not have a favorable effect on the therapeutic response to CLINORIL, the
combination is not recommended.
Cyclosporine
Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been
associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal
prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function
should be carefully monitored.
Diflunisal
The concomitant administration of CLINORIL and diflunisal in normal volunteers resulted in lowering
of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.
Diuretics
Clinical studies, as well as post marketing observations, have shown that CLINORIL can reduce the
natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to
inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should
be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure
diuretic efficacy.
DMSO
DMSO should not be used with sulindac. Concomitant administration has been reported to reduce the
plasma levels of the active sulfide metabolite and potentially reduce efficacy. In addition, this combination
has been reported to cause peripheral neuropathy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin
synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should
be observed carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices.
This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when
NSAIDs are administered concomitantly with methotrexate.
NSAIDs
The concomitant use of CLINORIL with other NSAIDs is not recommended due to the increased
possibility of gastrointestinal toxicity, with little or no increase in efficacy.
Oral anticoagulants
Although sulindac and its sulfide metabolite are highly bound to protein, studies in which CLINORIL
was given at a dose of 400 mg daily have shown no clinically significant interaction with oral
anticoagulants. However, patients should be monitored carefully until it is certain that no change in their
anticoagulant dosage is required. Special attention should be paid to patients taking higher doses than
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
those recommended and to patients with renal impairment or other metabolic defects that might increase
sulindac blood levels. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users
of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Oral hypoglycemic agents
Although sulindac and its sulfide metabolite are highly bound to protein, studies in which CLINORIL
was given at a dose of 400 mg daily, have shown no clinically significant interaction with oral
hypoglycemic agents. However, patients should be monitored carefully until it is certain that no change in
their hypoglycemic dosage is required. Special attention should be paid to patients taking higher doses
than those recommended and to patients with renal impairment or other metabolic defects that might
increase sulindac blood levels.
Probenecid
Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while
plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest
reduction in the uricosuric action of probenecid, which probably is not significant under most
circumstances.
Propoxyphene hydrochloride
Propoxyphene hydrochloride had no effect on the plasma levels of sulindac or its sulfide metabolite.
Pregnancy
Teratogenic Effects. Pregnancy Category C.
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental
abnormalities. However, animal reproduction studies are not always predictive of human response. There
are no adequate and well-controlled studies in pregnant women. CLINORIL should be used in pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
The known effects of drugs of this class on the human fetus during the third trimester of pregnancy
include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary
hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical
management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial
bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent
renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing
enterocolitis.
In reproduction studies in the rat, a decrease in average fetal weight and an increase in numbers of
dead pups were observed on the first day of the postpartum period at dosage levels of 20 and 40
mg/kg/day (2½ and 5 times the usual maximum daily dose in humans), although there was no adverse
effect on the survival and growth during the remainder of the postpartum period. CLINORIL prolongs the
duration of gestation in rats, as do other compounds of this class. Visceral and skeletal malformations
observed in low incidence among rabbits in some teratology studies did not occur at the same dosage
levels in repeat studies, nor at a higher dosage level in the same species.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of CLINORIL
on labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk; however, it is secreted in the milk of
lactating rats. Because many drugs are excreted in human milk and because of the potential for serious
adverse reactions in nursing infants from CLINORIL, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since
advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate
ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINORIL® (Sulindac)
are in this population (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and
Perforation).
CLINORIL is known to be substantially excreted by the kidney and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection and it may be useful to monitor
renal function (see WARNINGS, Renal Effects).
ADVERSE REACTIONS
The following adverse reactions were reported in clinical trials or have been reported since the drug
was marketed. The probability exists of a causal relationship between CLINORIL and these adverse
reactions. The adverse reactions which have been observed in clinical trials encompass observations in
1,865 patients, including 232 observed for at least 48 weeks.
Incidence Greater Than 1%
Gastrointestinal
The most frequent types of adverse reactions occurring with CLINORIL are gastrointestinal; these
include gastrointestinal pain (10%), dyspepsia***, nausea*** with or without vomiting, diarrhea***,
constipation***, flatulence, anorexia and gastrointestinal cramps.
Dermatologic
Rash***, pruritus.
Central Nervous System
Dizziness***, headache***, nervousness.
Special Senses
Tinnitus.
Miscellaneous
Edema (see WARNINGS).
Incidence Less Than 1 in 100
Gastrointestinal
Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI
perforation and intestinal strictures (diaphragms) have been reported rarely.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.
There have been rare reports of sulindac metabolites in common bile duct "sludge" and in biliary
calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy.
Pancreatitis (see PRECAUTIONS).
Ageusia; glossitis.
Dermatologic
Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.
Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative
dermatitis have been reported.
Cardiovascular
Congestive heart failure, especially in patients with marginal cardiac function; palpitation;
hypertension.
Hematologic
Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow
depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on oral
anticoagulants (see PRECAUTIONS).
Genitourinary
Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment,
including renal failure; interstitial nephritis; nephrotic syndrome.
Renal calculi containing sulindac metabolites have been observed rarely.
Metabolic
Hyperkalemia.
*** Incidence between 3% and 9%. Those reactions occurring in 1% to 3% of patients are not marked with an asterisk.
12
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CLINORIL® (Sulindac)
Musculoskeletal
Muscle weakness.
Psychiatric
Depression; psychic disturbances including acute psychosis.
Nervous System
Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis (especially in
patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, see
PRECAUTIONS).
Special Senses
Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste.
Respiratory
Epistaxis.
Hypersensitivity Reactions
Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea.
Hypersensitivity vasculitis.
A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include
constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other
dermatologic reactions ⎯ see above), conjunctivitis, involvement of major organs (changes in liver
function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion,
leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment,
including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue,
malaise, hypotension, chest pain, tachycardia).
Causal Relationship Unknown
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic
streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents,
sometimes with fatal outcome (see also PRECAUTIONS, General).
Other reactions have been reported in clinical trials or since the drug was marketed, but occurred
under circumstances where a causal relationship could not be established. However, in these rarely
reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as
alerting information to physicians.
Cardiovascular
Arrhythmia.
Metabolic
Hyperglycemia.
Nervous System
Neuritis.
Special Senses
Disturbances of the retina and its vasculature.
Miscellaneous
Gynecomastia.
MANAGEMENT OF OVERDOSAGE
Cases of overdosage have been reported and rarely, deaths have occurred. The following signs and
symptoms may be observed following overdosage: stupor, coma, diminished urine output and
hypotension.
In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage,
and the patient carefully observed and given symptomatic and supportive treatment.
Animal studies show that absorption is decreased by the prompt administration of activated charcoal
and excretion is enhanced by alkalinization of the urine.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of CLINORIL and other treatment options before
deciding to use CLINORIL. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
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CLINORIL® (Sulindac)
After observing the response to initial therapy with CLINORIL, the dose and frequency should be
adjusted to suit an individual patient’s needs.
CLINORIL should be administered orally twice a day with food. The maximum dosage is 400 mg per
day. Dosages above 400 mg per day are not recommended.
In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended starting dosage is
150 mg twice a day. The dosage may be lowered or raised depending on the response.
A prompt response (within one week) can be expected in about one-half of patients with osteoarthritis,
ankylosing spondylitis, and rheumatoid arthritis. Others may require longer to respond.
In acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis) and acute gouty
arthritis, the recommended dosage is 200 mg twice a day. After a satisfactory response has been
achieved, the dosage may be reduced according to the response. In acute painful shoulder, therapy for 7
14 days is usually adequate. In acute gouty arthritis, therapy for 7 days is usually adequate.
HOW SUPPLIED
No. 3353X ⎯ Tablets CLINORIL 200 mg are bright yellow, hexagon-shaped, compressed tablets, one
side full scored, the other side half scored and debossed MSD 942. They are supplied as follows:
NDC 0006-0942-68 in bottles of 100.
Storage
Store in a well-closed container at room temperature 15-30ºC (59-86ºF).
Rx Only
Manufactured for: compnay logo
By:
MERCK SHARP & DOHME Pty., Ltd.
South Granville, NSW, Australia 2142.
Issued MONTH YEAR
Printed in USA
14
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.
This chance increases:
•
with longer use of NSAID medicines
•
in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a “coronary
artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment.
Ulcers and bleeding:
•
can happen without warning symptoms
•
may cause death
The chance of a person getting an ulcer or bleeding increases with:
•
taking medicines called “corticosteroids” and “anticoagulants”
•
longer use
•
smoking
•
drinking alcohol
•
older age
•
having poor health
NSAID medicines should only be used:
•
exactly as prescribed
•
at the lowest dose possible for your treatment
•
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
•
different types of arthritis
•
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
•
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
•
for pain right before or after heart bypass surgery
Tell your healthcare provider:
•
about all of your medical conditions.
•
about all of the medicines you take. NSAIDs and some other medicines can interact with
each other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
if you are pregnant. NSAID medicines should not be used by pregnant women
late in their pregnancy.
•
if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling (fluid
retention)
•
kidney problems including kidney failure
•
bleeding and ulcers in the stomach and
intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver failure
•
asthma attacks in people who have asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
Get emergency help right away if you have any of the following symptoms:
•
shortness of breath or trouble breathing
•
slurred speech
•
chest pain
•
swelling of the face or throat
•
weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any of
the following symptoms:
•
nausea
•
there is blood in your bowel
•
more tired or weaker than usual
movement or it is black and
•
itching
sticky like tar
•
your skin or eyes look yellow
•
unusual weight gain
•
stomach pain
•
skin rash or blisters with fever
•
flu-like symptoms
•
swelling of the arms and legs,
•
vomit blood
hands and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
•
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack.
Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause
ulcers in the stomach and intestines.
•
Some of these NSAID medicines are sold in lower doses without a prescription (over-the
counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more
than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9676106
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbiprofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethegan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan,
Naprapac (copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is
usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term
continuous use may increase the risk of heart attack or stroke.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017911s073lbl.pdf', 'application_number': 17911, 'submission_type': 'SUPPL ', 'submission_number': 73}
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RETIN-A®
Cream Gel Liquid
(tretinoin)
For Topical Use Only
Prescribing Information
Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne
vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or
0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert-
butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of
three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl
myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified
water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and
alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid
and has the following structure:
Leave space for structure.
Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests
that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation.
Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing
extrusion of the comedones.
Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety
and efficacy of the long-term use of this product in the treatment of other disorders have not been established.
Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is
noted.
Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out
of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication
should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN-
A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened
susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun
exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of
sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided.
Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.
RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous
membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of
local irritation warrants, patients should be directed to use the medication less frequently, discontinue use
temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin
and should be used with utmost caution in patients with this condition.
Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and
cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or
lime should be used with caution because of possible interaction with tretinoin. Particular caution should be
exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to
“rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun.
Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were
administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in
the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was
observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035%
formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human
systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear
because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because
they were within the background natural occurrence rate for these tumors in this strain of mice. There was no
evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times
the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the
animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1%
RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential
of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study
in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05%
tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to
sunlight or artificial ultraviolet irradiation sources.
The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay,
both of which were negative.
In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant)
decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose
adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of
nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for
total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been
performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of
neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does
adjusted for total body surface area).
Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats,
mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or
topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body
surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the
cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal
malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times
the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were
observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have
also been reported in pigtail macaques.
Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity
(shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum
human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal
incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times
the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head
and hydrocephaly, typical of retinoid-induced fetal malformations in this species.
In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but
not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum
human systemic does adjusted for total body surface area in both species).
With widespread use of any drug, a small number of birth defect reports associated temporally with the
administration of the drug would be expected by chance alone. Thirty human cases of temporally associated
congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite
pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe
the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the
forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.
Nonteratogenic effects:
Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum
human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting
in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the
maximum human systemic dose adjusted for total body surface area).
There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when RETIN-A is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established.
Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of
RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered,
or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is
restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical
tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application
of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under
treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of
therapy (see Dosage and Administration Section).
Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked
redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those
associated with excessive oral intake of Vitamin A.
Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the
skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be
applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to
oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive
application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient.
Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to
temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of
application increased when the patients become able to tolerate the treatment.
Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of
the clinical therapeutic response and skin tolerance.
During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the
action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue
therapy.
Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required
before definite beneficial effects are seen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less
frequent applications, or other dosage forms.
Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be
cleansed thoroughly before the medication is applied. (See Precautions)
How Supplied:
RETIN-A (tretinoin) is supplied as:
RETIN-A Cream
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0165-01
0.025% Cream
20g
0062-0165-02
0.025% Cream
45g
0062-0175-12
0.05% Cream
20g
0062-0175-13
0.05% Cream
45g
0062-0275-23
0.1% Cream
20g
0062-0275-01
0.1% Cream
45g
RETIN-A Gel
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0575-44
0.01% Gel
15g
0062-0575-46
0.01% Gel
45g
0062-0475-42
0.025% Gel
15g
0062-0475-45
0.025% Gel
45g
RETIN-A Liquid
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0075-07
0.05% Liquid
28 mL
Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN-
A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ortho Dermatological
(new logo)
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETIN-A®
PATIENT INSTRUCTIONS Cream Gel Liquid
(tretinoin)
Acne Treatment
For Topical Use Only
IMPORTANT
Read Directions Carefully Before Using
THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED
BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S
INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO
OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS
PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY
QUESTIONS, BE SURE TO ASK YOUR DOCTOR.
WARNINGS
RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of
reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C).
PRECAUTIONS
The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a
sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and
even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care
taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn
and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized.
Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors.
These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated
with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice
treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was
reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either
laboratory animals or humans. However, investigations in this area are continuing.
Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An
effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an
SPF level which will provide you with the necessary high level of protection). For extended sun exposure,
protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you
do become sunburned, stop your therapy with RETIN-A until your skin has recovered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated
with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your
acne treatment under such conditions.
Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or
crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your
physician.
There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or
decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when
the skin was allowed to adjust to RETIN-A or therapy was discontinued.
Use other medication only on your physician’s advice. Only your physician knows which other medications
may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions
carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may
include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and
hair permanent solutions. Do not allow anyone else to use this medication.
Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you
have used in the past might cause unnecessary redness or peeling.
If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in
humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are
nursing a baby, consult your physician before using the medication.
AND WHILE YOU’RE ON RETIN-A THERAPY
Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no
matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times
actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be
sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician,
etc., may worsen your acne.
HOW TO USE RETIN-A (TRETINOIN)
To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given
for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be
patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN,
FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF
YOU HAVE QUESTIONS, ASK YOU DOCTOR.
To help you use the medication correctly, keep these simple instructions in mind.
(Insert picture)
•
Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise,
especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First,
wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING
MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation.
•
It is better not to use more than the amount suggested by your physician or to apply more frequently than
instructed. Too much may irritate the skin, waste medication and won’t give faster or better results.
•
Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from
these areas when applying.
•
RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be
enough for your whole face, after you have some experience with the medication you may find you need
slightly more or less to do the job. The medication should become invisible almost immediately. If it is still
visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first
dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth
gently into the skin.
•
RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough
for your whole face, after you have some experience with the medication you may find you need slightly more
or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry
flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with
RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over
the entire affected are. Smooth gently into the skin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear,
spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or
cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area
where treatment is not intended (such as corners of the mouth, eyes, and nose).
•
It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your
acne (noncomedogenic) every morning after you wash.
WHAT TO EXPECT WITH YOUR NEW TREATMENT
RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying
more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient.
There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their
skin begins to take on a blush.
These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually
subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully.
Should the effects become excessively troublesome, consult your doctor.
BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At
this stage it is important to continue using RETIN-A.
If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your
appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop
treatment at the first signs of improvement.
Once your acne is under control you should continue regular application of RETIN-A until your physician instructs
otherwise.
IF YOU HAVE QUESTIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A
(tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday
through Friday.
Ortho Dermatological
(new logo)
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Markham Luke
6/10/02 11:40:52 AM
Acting for Dr. Jonathan Wilkin, Division Director, DDDDP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:44:24.774516
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 17955, 'submission_type': 'SUPPL ', 'submission_number': 20}
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11,095
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RETIN-A®
Cream Gel Liquid
(tretinoin)
For Topical Use Only
Prescribing Information
Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne
vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or
0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert-
butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of
three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl
myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified
water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and
alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid
and has the following structure:
Leave space for structure.
Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests
that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation.
Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing
extrusion of the comedones.
Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety
and efficacy of the long-term use of this product in the treatment of other disorders have not been established.
Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is
noted.
Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out
of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication
should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN-
A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened
susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun
exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of
sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided.
Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.
RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous
membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of
local irritation warrants, patients should be directed to use the medication less frequently, discontinue use
temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin
and should be used with utmost caution in patients with this condition.
Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and
cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or
lime should be used with caution because of possible interaction with tretinoin. Particular caution should be
exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to
“rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun.
Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were
administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in
the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was
observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035%
formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human
systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear
because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because
they were within the background natural occurrence rate for these tumors in this strain of mice. There was no
evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times
the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the
animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1%
RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential
of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study
in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05%
tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to
sunlight or artificial ultraviolet irradiation sources.
The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay,
both of which were negative.
In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant)
decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose
adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of
nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for
total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been
performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of
neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does
adjusted for total body surface area).
Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats,
mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or
topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body
surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the
cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal
malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times
the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were
observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have
also been reported in pigtail macaques.
Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity
(shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum
human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal
incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times
the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head
and hydrocephaly, typical of retinoid-induced fetal malformations in this species.
In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but
not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum
human systemic does adjusted for total body surface area in both species).
With widespread use of any drug, a small number of birth defect reports associated temporally with the
administration of the drug would be expected by chance alone. Thirty human cases of temporally associated
congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite
pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe
the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the
forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.
Nonteratogenic effects:
Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum
human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting
in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the
maximum human systemic dose adjusted for total body surface area).
There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when RETIN-A is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established.
Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of
RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered,
or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is
restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical
tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application
of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under
treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of
therapy (see Dosage and Administration Section).
Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked
redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those
associated with excessive oral intake of Vitamin A.
Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the
skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be
applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to
oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive
application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient.
Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to
temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of
application increased when the patients become able to tolerate the treatment.
Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of
the clinical therapeutic response and skin tolerance.
During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the
action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue
therapy.
Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required
before definite beneficial effects are seen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less
frequent applications, or other dosage forms.
Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be
cleansed thoroughly before the medication is applied. (See Precautions)
How Supplied:
RETIN-A (tretinoin) is supplied as:
RETIN-A Cream
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0165-01
0.025% Cream
20g
0062-0165-02
0.025% Cream
45g
0062-0175-12
0.05% Cream
20g
0062-0175-13
0.05% Cream
45g
0062-0275-23
0.1% Cream
20g
0062-0275-01
0.1% Cream
45g
RETIN-A Gel
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0575-44
0.01% Gel
15g
0062-0575-46
0.01% Gel
45g
0062-0475-42
0.025% Gel
15g
0062-0475-45
0.025% Gel
45g
RETIN-A Liquid
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0075-07
0.05% Liquid
28 mL
Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN-
A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ortho Dermatological
(new logo)
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETIN-A®
PATIENT INSTRUCTIONS Cream Gel Liquid
(tretinoin)
Acne Treatment
For Topical Use Only
IMPORTANT
Read Directions Carefully Before Using
THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED
BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S
INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO
OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS
PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY
QUESTIONS, BE SURE TO ASK YOUR DOCTOR.
WARNINGS
RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of
reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C).
PRECAUTIONS
The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a
sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and
even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care
taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn
and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized.
Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors.
These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated
with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice
treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was
reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either
laboratory animals or humans. However, investigations in this area are continuing.
Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An
effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an
SPF level which will provide you with the necessary high level of protection). For extended sun exposure,
protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you
do become sunburned, stop your therapy with RETIN-A until your skin has recovered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated
with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your
acne treatment under such conditions.
Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or
crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your
physician.
There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or
decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when
the skin was allowed to adjust to RETIN-A or therapy was discontinued.
Use other medication only on your physician’s advice. Only your physician knows which other medications
may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions
carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may
include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and
hair permanent solutions. Do not allow anyone else to use this medication.
Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you
have used in the past might cause unnecessary redness or peeling.
If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in
humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are
nursing a baby, consult your physician before using the medication.
AND WHILE YOU’RE ON RETIN-A THERAPY
Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no
matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times
actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be
sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician,
etc., may worsen your acne.
HOW TO USE RETIN-A (TRETINOIN)
To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given
for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be
patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN,
FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF
YOU HAVE QUESTIONS, ASK YOU DOCTOR.
To help you use the medication correctly, keep these simple instructions in mind.
(Insert picture)
•
Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise,
especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First,
wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING
MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation.
•
It is better not to use more than the amount suggested by your physician or to apply more frequently than
instructed. Too much may irritate the skin, waste medication and won’t give faster or better results.
•
Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from
these areas when applying.
•
RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be
enough for your whole face, after you have some experience with the medication you may find you need
slightly more or less to do the job. The medication should become invisible almost immediately. If it is still
visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first
dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth
gently into the skin.
•
RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough
for your whole face, after you have some experience with the medication you may find you need slightly more
or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry
flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with
RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over
the entire affected are. Smooth gently into the skin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear,
spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or
cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area
where treatment is not intended (such as corners of the mouth, eyes, and nose).
•
It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your
acne (noncomedogenic) every morning after you wash.
WHAT TO EXPECT WITH YOUR NEW TREATMENT
RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying
more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient.
There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their
skin begins to take on a blush.
These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually
subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully.
Should the effects become excessively troublesome, consult your doctor.
BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At
this stage it is important to continue using RETIN-A.
If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your
appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop
treatment at the first signs of improvement.
Once your acne is under control you should continue regular application of RETIN-A until your physician instructs
otherwise.
IF YOU HAVE QUESTIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A
(tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday
through Friday.
Ortho Dermatological
(new logo)
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Markham Luke
6/10/02 11:40:52 AM
Acting for Dr. Jonathan Wilkin, Division Director, DDDDP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:24.995982
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 17955, 'submission_type': 'SUPPL ', 'submission_number': 19}
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11,094
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DDAVP®
Nasal Spray
(desmopressin acetate)
Rx only
DESCRIPTION
DDAVP® Nasal Spray (desmopressin acetate) is a synthetic analogue of the natural pituitary
hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water
conservation. It is chemically defined as follows:
Mol. wt. 1183.34
Empirical formula: C46H64N14O12S2•C2H4O2•3H2O
1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
DDAVP Nasal Spray is provided as an aqueous solution for intranasal use.
Each mL contains:
Desmopressin acetate
0.1 mg
Sodium Chloride
7.5 mg
Citric acid monohydrate
1.7 mg
Disodium phosphate dihydrate
3.0 mg
Benzalkonium chloride solution (50%)
0.2 mg
The DDAVP Nasal Spray compression pump delivers 0.1 mL (10 mcg) of DDAVP
(desmopressin acetate) per spray.
CLINICAL PHARMACOLOGY
DDAVP contains as active substance desmopressin acetate, a synthetic analogue of the natural
hormone arginine vasopressin. One mL (0.1 mg) of intranasal DDAVP has an antidiuretic
activity of about 400 IU; 10 mcg of desmopressin acetate is equivalent to 40 IU.
1. The biphasic half-lives for intranasal DDAVP were 7.8 and 75.5 minutes for the fast and
slow phases, compared with 2.5 and 14.5 minutes for lysine vasopressin, another form of the
hormone used in this condition. As a result, intranasal DDAVP provides a prompt onset of
antidiuretic action with a long duration after each administration.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. The change in structure of arginine vasopressin to DDAVP has resulted in a decreased
vasopressor action and decreased actions on visceral smooth muscle relative to the enhanced
antidiuretic activity, so that clinically effective antidiuretic doses are usually below threshold
levels for effects on vascular or visceral smooth muscle.
3. DDAVP administered intranasally has an antidiuretic effect about one-tenth that of an
equivalent dose administered by injection.
Human Pharmacokinetics: DDAVP is mainly excreted in the urine. A pharmacokinetic study
conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment (n=24,
6 subjects in each group) receiving single dose desmopressin acetate (2mcg) injection demonstrated a
difference in DDAVP terminal half-life. Terminal half-life significantly increased from 3 hours in
normal healthy patients to 9 hours in patients with severe renal impairment. (See
CONTRAINDICATIONS.)
INDICATIONS AND USAGE
Central Cranial Diabetes Insipidus: DDAVP Nasal Spray is indicated as antidiuretic
replacement therapy in the management of central cranial diabetes insipidus and for management
of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary
region. It is ineffective for the treatment of nephrogenic diabetes insipidus.
The use of DDAVP Nasal Spray in patients with an established diagnosis will result in a
reduction in urinary output with increase in urine osmolality and a decrease in plasma
osmolality. This will allow the resumption of a more normal life-style with a decrease in urinary
frequency and nocturia.
There are reports of an occasional change in response with time, usually greater than
6 months. Some patients may show a decreased responsiveness, others a shortened duration of
effect. There is no evidence this effect is due to the development of binding antibodies but may
be due to a local inactivation of the peptide.
Patients are selected for therapy by establishing the diagnosis by means of the water deprivation
test, the hypertonic saline infusion test, and/or the response to antidiuretic hormone. Continued
response to intranasal DDAVP can be monitored by urine volume and osmolality.
DDAVP is also available as a solution for injection when the intranasal route may be
compromised. These situations include nasal congestion and blockage, nasal discharge, atrophy
of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may also be inappropriate
where there is an impaired level of consciousness. In addition, cranial surgical procedures, such
as transsphenoidal hypophysectomy create situations where an alternative route of administration
is needed as in cases of nasal packing or recovery from surgery.
CONTRAINDICATIONS
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DDAVP Nasal Spray is contraindicated in individuals with known hypersensitivity to
desmopressin acetate or to any of the components of DDAVP Nasal Spray.
DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as a
creatinine clearance below 50ml/min).
DDAVP is contraindicated in patients with hyponatremia or a history of hyponatremia.
WARNINGS
1. For intranasal use only.
2. DDAVP Nasal Spray should only be used in patients where orally administered
formulations are not feasible.
3. Very rare cases of hyponatremia have been reported from world-wide postmarketing
experience in patients treated with DDAVP (desmopressin acetate). DDAVP is a potent
antidiuretic which, when administered, may lead to water intoxication and/or hyponatremia.
Unless properly diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction
is recommended and should be discussed with the patient and/or guardian. Careful medical
supervision is required.
4. When DDAVP Nasal Spray is administered, in particular in pediatric and geriatric patients,
fluid intake should be adjusted downward in order to decrease the potential occurrence of
water intoxication and hyponatremia (See PRECAUTIONS, Pediatric Use and Geriatric
Use.) All patients receiving DDAVP therapy should be observed for the following signs or
symptoms associated with hyponatremia: headache, nausea/vomiting, decreased serum
sodium weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss of
appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status
such as hallucinations, decreased consciousness and confusion. Severe symptoms may
include one or a combination of the following: seizure, coma and/or respiratory arrest.
Particular attention should be paid to the possibility of the rare occurrence of an extreme
decrease in plasma osmolality that may result in seizures which could lead to coma.
5. DDAVP should be used with caution in patients with habitual or psychogenic polydipsia who
may be more likely to drink excessive amounts of water, putting them at greater risk of
hyponatremia.
PRECAUTIONS
General: Intranasal DDAVP at high dosage has infrequently produced a slight elevation of
blood pressure, which disappeared with a reduction in dosage. The drug should be used with
caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease
because of possible rise in blood pressure.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DDAVP should be used with caution in patients with conditions associated with fluid and
electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders because these
patients are prone to hyponatremia.
Rare severe allergic reactions have been reported with DDAVP. Anaphylaxis has been reported
rarely with intravenous and intranasal administration of DDAVP.
Central Cranial Diabetes Insipidus: Since DDAVP is used intranasally, changes in the nasal
mucosa such as scarring, edema, or other disease may cause erratic, unreliable absorption in
which case intranasal DDAVP should not be used. For such situations, DDAVP Injection should
be considered.
Information for Patients: Ensure that in children administration is under adult supervision
in order to control the dose intake. Patients should be informed that the DDAVP Nasal Spray
bottle accurately delivers 50 doses of 10 mcg each. Any solution remaining after 50 doses should
be discarded since the amount delivered thereafter may be substantially less than 10 mcg of drug.
No attempt should be made to transfer remaining solution to another bottle. Patients should be
instructed to read accompanying directions on use of the spray pump carefully before use.
Fluid intake should be adjusted downward based upon discussion with the physician.
Laboratory Tests: Laboratory tests for following the patient with central cranial diabetes
insipidus or post-surgical or head trauma-related polyuria and polydipsia include urine volume
and osmolality. In some cases plasma osmolality measurements may be required.
Drug Interactions: Although the pressor activity of DDAVP is very low compared to the
antidiuretic activity, use of large doses of intranasal DDAVP with other pressor agents should
only be done with careful patient monitoring. The concomitant administration of drugs that may
increase the risk of water intoxication with hyponatremia, (e.g. tricyclic antidepressants,
selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine
and carbamazepine) should be performed with caution.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with DDAVP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Category B: Fertility studies have not been done. Teratology studies in rats and
rabbits at doses from 0.05 to 10 mcg/kg/day (approximately 0.1 times the maximum systemic
human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits
based on surface area, mg/m2) revealed no harm to the fetus due to DDAVP (desmopressin
acetate). There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.
Several publications of desmopressin acetate’s use in the management of diabetes insipidus
during pregnancy are available; these include a few anecdotal reports of congenital anomalies
and low birth weight babies. However, no causal connection between these events and
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
desmopressin acetate has been established. A fifteen year Swedish epidemiologic study of the
use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth
defects to be no greater than that in the general population; however, the statistical power of this
study is low. As opposed to preparations containing natural hormones, desmopressin acetate in
antidiuretic doses has no uterotonic action and the physician will have to weigh the therapeutic
advantages against the possible risks in each case.
Nursing Mothers: There have been no controlled studies in nursing mothers. A single study in a
post-partum woman demonstrated a marked change in plasma, but little if any change in
assayable DDAVP in breast milk following an intranasal dose of 10 mcg. It is not known
whether this drug is excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when DDAVP is administered to a nursing woman.
Pediatric Use: Central Cranial Diabetes Insipidus: DDAVP Nasal Spray has been used in
children with diabetes insipidus. Use in infants and children will require careful fluid intake
restriction to prevent possible hyponatremia and water intoxication. (See WARNINGS.) The
dose must be individually adjusted to the patient with attention in the very young to the danger of
an extreme decrease in plasma osmolality with resulting convulsions. Dose should start at 0.05
mL or less.
Since the spray cannot deliver less than 0.1 mL (10 mcg), smaller doses should be administered
using the rhinal tube delivery system. Do not use the nasal spray in pediatric patients requiring
less than 0.1 mL (10 mcg) per dose.
Geriatric Use: Clinical studies of DDAVP Nasal Spray did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly
and younger subjects. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function. DDAVP is contraindicated in patients with moderate to
severe renal impairment (defined as a creatinine clearance below 50ml/min). (See CLINICAL
PHARMACOLOGY, Human Pharmacokinetics and CONTRAINDICATIONS.)
Use of DDAVP Nasal Spray in geriatric patients will require careful fluid intake restriction to
prevent possible hyponatremia and water intoxication. (See WARNINGS).
There are reports of an occasional change in response with time, usually greater than 6 months.
Some patients may show a decreased responsiveness, others a shortened duration of effect. There
is no evidence this effect is due to the development of binding antibodies but may be due to a
local inactivation of the peptide.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Infrequently, high dosages of intranasal DDAVP have produced transient headache and nausea.
Nasal congestion, rhinitis and flushing have also been reported occasionally along with mild
abdominal cramps. These symptoms disappeared with reduction in dosage. Nosebleed, sore
throat, cough and upper respiratory infections have also been reported.
The following table lists the percentage of patients having adverse experiences without regard to
relationship to study drug from the pooled pivotal study data for nocturnal enuresis.
DDAVP
DDAVP
PLACEBO
20 mcg
40 mcg
ADVERSE REACTION
(N=59)
(N=60)
(N=61)
%
%
%
BODY AS A WHOLE
Abdominal Pain
0
2
2
Asthenia
0
0
2
Chills
0
0
2
Headache
0
2
5
NERVOUS SYSTEM
Dizziness
RESPIRATORY SYSTEM
Epistaxis
Nostril Pain
Rhinitis
DIGESTIVE SYSTEM
Gastrointestinal Disorder
Nausea
SPECIAL SENSES
Conjunctivitis
Edema Eyes
Lachrymation Disorder
0
2
0
2
0
0
0
0
0
0
3
2
8
2
0
2
2
0
3
0
0
3
0
2
0
0
2
Post Marketing: There have been rare reports of hyponatremic convulsions associated with
concomitant use with the following medications: oxybutinin and imipramine.
See WARNINGS for the possibility of water intoxication and hyponatremia.
OVERDOSAGE
Signs of overdose may include confusion, drowsiness, continuing headache, problems with
passing urine and rapid weight gain due to fluid retention. (See WARNINGS.) In case of
overdosage, the dose should be reduced, frequency of administration decreased, or the drug
withdrawn according to the severity of the condition. There is no known specific antidote for
desmopressin acetate or DDAVP Nasal Spray.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
An oral LD50 has not been established. An intravenous dose of 2 mg/kg in mice demonstrated no
effect.
DOSAGE AND ADMINISTRATION
Central Cranial Diabetes Insipidus: DDAVP Nasal Spray dosage must be determined for
each individual patient and adjusted according to the diurnal pattern of response. Response
should be estimated by two parameters: adequate duration of sleep and adequate, not excessive,
water turnover. Patients with nasal congestion and blockage have often responded well to
intranasal DDAVP. The usual dosage range in adults is 0.1 to 0.4 mL daily, either as a single
dose or divided into two or three doses. Most adults require 0.2 mL daily in two divided doses.
The morning and evening doses should be separately adjusted for an adequate diurnal rhythm of
water turnover. For children aged 3 months to 12 years, the usual dosage range is 0.05 to 0.3 mL
daily, either as a single dose or divided into two doses. About 1/4 to 1/3 of patients can be
controlled by a single daily dose of DDAVP administered intranasally. Fluid restriction should
be observed. (See WARNINGS, PRECAUTIONS, Pediatric Use and Geriatric Use.)
The nasal spray pump can only deliver doses of 0.1 mL (10 mcg) or multiples of 0.1 mL. If doses
other than these are required, the rhinal tube delivery system may be used.
The spray pump must be primed prior to the first use. To prime pump, press down four times.
The bottle will now deliver 10 mcg of drug per spray. Discard DDAVP Nasal Spray after 50
sprays since the amount delivered thereafter per spray may be substantially less than 10 µg of
drug.
Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of
toxic reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY, Human Pharmacokinetics, CONTRAINDICATIONS, and
PRECAUTIONS, Geriatric Use.)
HOW SUPPLIED
DDAVP Nasal Spray is available in a 5-mL bottle with spray pump delivering 50 sprays of 10
mcg (NDC 0075-2452-01). Desmopressin acetate is also available as DDAVP Rhinal Tube, a
refrigerated product with 2.5 mL per bottle, packaged with two rhinal tube applicators per carton
(NDC 0075-2450-01).
Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP]. STORE BOTTLE IN
UPRIGHT POSITION.
Keep out of the reach of children.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
U.S. Patent Nos. 5,498,598; 5,500,413; 5,596,078; 5,674,850; 5,763,407
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Rev. July 2007
©2007 sanofi-aventis U.S. LLC
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INSTRUCTION GUIDE
DDAVP® Nasal Spray
(desmopressin acetate)
A better way to deliver DDAVP
Delivering DDAVP more efficiently
Your doctor has prescribed DDAVP as antidiuretic hormone replacement therapy. Follow the
dosage schedule that is specified. The convenient nasal spray pump provides an efficient, reliable
way to administer your medication. It is important, however, to adhere completely to the
following instructions so that you will always receive a consistent dose of your medication.
CAUTION: The nasal spray pump accurately delivers 50 doses of 10 micrograms each. Any
solution remaining after 50 doses should be discarded since the amount delivered thereafter per
actuation may be substantially less than 10 micrograms of drug. Do not transfer any remaining
solution to another bottle. Please read the following instructions carefully before using the spray
pump.
Ensure that in children administration is under adult supervision in order to control the
dose intake.
If you accidentally deliver/administer too much of a dose, immediately telephone your doctor or
a certified Regional Poison Center for advice. Possible signs of overdose may include confusion,
drowsiness, continuing headache, problems with passing urine and rapid weight gain due to fluid
retention.
Using your DDAVP Nasal Spray Pump
1. Remove protective cap.
2. The spray pump must be primed prior to the first use. To prime pump, press down 4
times.
3. Once primed, the spray pump delivers 10 micrograms of medication each time it is pressed.
To ensure dosing accuracy, tilt bottle so that dip tube inside the bottle draws from the deepest
portion of the medication.
CORRECT
INCORRECT
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To administer a 10-microgram dose, place the spray nozzle in nostril and press the spray pump
once. If a higher dose has been prescribed, spray half the dose in each nostril. The spray pump
cannot be used for doses less than 10 micrograms or doses other than multiples of 10
micrograms.
4. Replace the protective cap on bottle after use. The pump will stay primed for up to one week.
If the product has not been used for a period of one week, re-prime the pump by pressing
once.
5. We have included a convenient check-off chart to assist you in keeping track of medication
doses used. This will help assure that you receive 50 “full doses” of medication. Please note
that the bottle has been filled with extra solution to accommodate the initial priming activity.
DDAVP Nasal Spray
50-Dose Check-off
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
1. Retain with medication or affix in convenient location.
2. Starting with dose #1, check off after each administration.
3. Discard medication after 50 doses.
Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP].
STORE BOTTLE IN UPRIGHT POSITION.
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Rev. July 2007
©2007 sanofi-aventis U.S. LLC
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DDAVP®
Rhinal Tube
(desmopressin acetate)
Rx only
DESCRIPTION
DDAVP® Rhinal Tube (desmopressin acetate) is a synthetic analogue of the natural pituitary
hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water
conservation. It is chemically defined as follows:
Mol. wt. 1183.34
Empirical formula: C46H64N14O12S2•C2H4O2•3H2O
1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
DDAVP Rhinal Tube is provided as an aqueous solution for intranasal use.
Each mL contains:
Desmopressin acetate
0.1 mg
Chlorobutanol
5.0 mg
Sodium Chloride
9.0 mg
Hydrochloric acid to adjust pH to approximately 4
CLINICAL PHARMACOLOGY
DDAVP Rhinal Tube contains as active substance desmopressin acetate, a synthetic analogue
of the natural hormone arginine vasopressin. One mL (0.1 mg) of intranasal DDAVP
(desmopressin acetate) has an antidiuretic activity of about 400 IU; 10 mcg of desmopressin
acetate is equivalent to 40 IU.
1. The biphasic half-lives for intranasal DDAVP were 7.8 and 75.5 minutes for the fast and
slow phases, compared with 2.5 and 14.5 minutes for lysine vasopressin, another form of the
hormone used in this condition. As a result, intranasal DDAVP provides a prompt onset of
antidiuretic action with a long duration after each administration.
2. The change in structure of arginine vasopressin to DDAVP has resulted in a decreased
vasopressor action and decreased actions on visceral smooth muscle relative to the enhanced
antidiuretic activity, so that clinically effective antidiuretic doses are usually below threshold
levels for effects on vascular or visceral smooth muscle.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3. DDAVP administered intranasally has an antidiuretic effect about one-tenth that of an
equivalent dose administered by injection.
Human Pharmacokinetics: DDAVP is mainly excreted in the urine. A pharmacokinetic study
conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment (n=24,
6 subjects in each group) receiving single dose desmopressin acetate (2mcg) injection demonstrated a
difference in DDAVP terminal half-life. Terminal half-life significantly increased from 3 hours in
normal healthy patients to 9 hours in patients with severe renal impairment. (See
CONTRAINDICATIONS.)
INDICATIONS AND USAGE
Central Cranial Diabetes Insipidus: DDAVP Rhinal Tube is indicated as antidiuretic
replacement therapy in the management of central cranial diabetes insipidus and for management
of the temporary polyuria and polydipsia following head trauma or surgery in the pituitary
region. It is ineffective for the treatment of nephrogenic diabetes insipidus.
The use of DDAVP Rhinal Tube in patients with an established diagnosis will result in a
reduction in urinary output with increase in urine osmolality and a decrease in plasma
osmolality. This will allow the resumption of a more normal life-style with a decrease in urinary
frequency and nocturia.
There are reports of an occasional change in response with time, usually greater than 6 months.
Some patients may show a decreased responsiveness, others a shortened duration of effect. There
is no evidence this effect is due to the development of binding antibodies but may be due to a
local inactivation of the peptide.
Patients are selected for therapy by establishing the diagnosis by means of the water deprivation
test, the hypertonic saline infusion test, and/or the response to antidiuretic hormone. Continued
response to intranasal DDAVP can be monitored by urine volume and osmolality.
DDAVP is also available as a solution for injection when the intranasal route may be
compromised. These situations include nasal congestion and blockage, nasal discharge, atrophy
of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may also be inappropriate
where there is an impaired level of consciousness. In addition, cranial surgical procedures, such
as transsphenoidal hypophysectomy create situations where an alternative route of administration
is needed as in cases of nasal packing or recovery from surgery.
CONTRAINDICATIONS
DDAVP Rhinal Tube is contraindicated in individuals with known hypersensitivity to
desmopressin acetate or to any of the components of DDAVP Rhinal Tube.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as a
creatinine clearance below 50ml/min).
DDAVP is contraindicated in patients with hyponatremia or a history of hyponatremia.
WARNINGS
1. For intranasal use only.
2. DDAVP Rhinal Tube should only be used in patients where orally administered
formulations are not feasible.
3. Very rare cases of hyponatremia have been reported from world-wide postmarketing
experience in patients treated with DDAVP (desmopressin acetate). DDAVP is a potent
antidiuretic which, when administered, may lead to water intoxication and/or hyponatremia.
Unless properly diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction
is recommended and should be discussed with the patient and/or guardian. Careful medical
supervision is required.
4. When DDAVP is administered, in particular, in pediatric and geriatric patients, fluid intake
should be adjusted downward in order to decrease the potential occurrence of water
intoxication and hyponatremia (See PRECAUTIONS, Pediatric Use and Geriatric Use.) All
patients receiving DDAVP therapy should be observed for the following signs or symptoms
associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium weight
gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss of appetite,
irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as
hallucinations, decreased consciousness and confusion. Severe symptoms may include one or
a combination of the following: seizure, coma and/or respiratory arrest. Particular attention
should be paid to the possibility of the rare occurrence of an extreme decrease in plasma
osmolality that may result in seizures which could lead to coma.
5. DDAVP should be used with caution in patients with habitual or psychogenic polydipsia who
may be more likely to drink excessive amounts of water, putting them at greater risk of
hyponatremia.
PRECAUTIONS
General: Intranasal DDAVP at high dosage has infrequently produced a slight elevation of
blood pressure, which disappeared with a reduction in dosage. The drug should be used with
caution in patients with coronary artery insufficiency and/or hypertensive cardiovascular disease
because of possible rise in blood pressure.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DDAVP should be used with caution in patients with conditions associated with fluid and
electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders because these
patients are prone to hyponatremia.
Ensure that in children administration is under adult supervision in order to control the
dose intake.
Rare severe allergic reactions have been reported with DDAVP. Anaphylaxis has been reported
rarely with intravenous and intranasal administration of DDAVP.
Central Cranial Diabetes Insipidus: Since DDAVP Rhinal Tube is used intranasally, changes
in the nasal mucosa such as scarring, edema, or other disease may cause erratic, unreliable
absorption in which case intranasal DDAVP should not be used. For such situations, DDAVP
Injection should be considered.
Laboratory Tests: Laboratory tests for following the patient with central cranial diabetes
insipidus or post-surgical or head trauma-related polyuria and polydipsia include urine volume
and osmolality. In some cases plasma osmolality measurements may be required.
Drug Interactions: Although the pressor activity of DDAVP is very low compared to the
antidiuretic activity, use of large doses of intranasal DDAVP with other pressor agents should
only be done with careful patient monitoring. The concomitant administration of drugs that may
increase the risk of water intoxication with hyponatremia, (e.g., tricyclic antidepressants, selective
serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine and
carbamazepine) should be performed with caution.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with DDAVP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy Category B: Fertility studies have not been done. Teratology studies in rats and
rabbits at doses from 0.05 to 10 mcg/kg/day (approximately 0.1 times the maximum systemic
human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits
based on surface area, mg/m2) revealed no harm to the fetus due to DDAVP. There are, however,
no adequate and well controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during pregnancy only if
clearly needed.
Several publications of desmopressin acetate’s use in the management of diabetes insipidus
during pregnancy are available; these include a few anecdotal reports of congenital anomalies
and low birth weight babies. However, no causal connection between these events and
desmopressin acetate has been established. A fifteen year, Swedish epidemiologic study of the
use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth
defects to be no greater than that in the general population; however the statistical power of this
study is low. As opposed to preparations containing natural hormones, desmopressin acetate in
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
antidiuretic doses has no uterotonic action and the physician will have to weigh the therapeutic
advantages against the possible risks in each case.
Nursing Mothers: There have been no controlled studies in nursing mothers. A single study in
postpartum women demonstrated a marked change in plasma, but little if any change in
assayable DDAVP (desmopressin acetate) in breast milk following an intranasal dose of 10 mcg.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when DDAVP is administered to a nursing woman.
Pediatric Use: Central Cranial Diabetes Insipidus: DDAVP Rhinal Tube has been used in
pediatric patients with diabetes insipidus. Use in infants and pediatric patients will require
careful fluid intake restriction to prevent possible hyponatremia and water intoxication. Fluid
restriction should be discussed with the patient and/or guardian. (See WARNINGS.) The dose must
be individually adjusted to the patient with attention in the very young to the danger of an
extreme decrease in plasma osmolality with resulting convulsions. Dose should start at 0.05 mL
or less.
There are reports of an occasional change in response with time, usually greater than 6 months.
Some patients may show a decreased responsiveness, others a shortened duration of effect. There
is no evidence this effect is due to the development of binding antibodies but may be due to a
local inactivation of the peptide.
Geriatric Use: Clinical studies of DDAVP Rhinal Tube did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function. DDAVP is contraindicated in patients with moderate to
severe renal impairment (defined as a creatinine clearance below 50ml/min). (See CLINICAL
PHARMACOLOGY, Human Pharmacokinetics and CONTRAINDICATIONS.)
Use of DDAVP Rhinal Tube in geriatric patients will require careful fluid intake restrictions to
prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with
the patient. (See WARNINGS.)
ADVERSE REACTIONS
Infrequently, high dosages of intranasal DDAVP have produced transient headache and nausea.
Nasal congestion, rhinitis and flushing have also been reported occasionally along with mild
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
abdominal cramps. These symptoms disappeared with reduction in dosage. Nosebleed, sore
throat, cough and upper respiratory infections have also been reported.
The following table lists the percent of patients having adverse experiences without regard to
relationship to study drug from the pooled pivotal study data for nocturnal enuresis.
DDAVP
DDAVP
PLACEBO
20 mcg
40 mcg
ADVERSE REACTION
(N=59)
(N=60)
(N=61)
%
%
%
BODY AS A WHOLE
Abdominal Pain
0
2
2
Asthenia
0
0
2
Chills
0
0
2
Headache
0
2
5
NERVOUS SYSTEM
Dizziness
RESPIRATORY SYSTEM
Epistaxis
Nostril Pain
Rhinitis
DIGESTIVE SYSTEM
Gastrointestinal Disorder
Nausea
SPECIAL SENSES
Conjunctivitis
Edema Eyes
Lachrymation Disorder
0
2
0
2
0
0
0
0
0
0
3
2
8
2
0
2
2
0
3
0
0
3
0
2
0
0
2
Post Marketing: There have been rare reports of hyponatremic convulsions associated with
concomitant use with the following medications: oxybutinin and imipramine.
See WARNINGS for the possibility of water intoxication and hyponatremia.
OVERDOSAGE
Signs of overdose may include confusion, drowsiness, continuing headache, problems with
passing urine and rapid weight gain due to fluid retention. (See WARNINGS.) In case of
overdosage, the dose should be reduced, frequency of administration decreased, or the drug
withdrawn according to the severity of the condition. There is no known specific antidote for
desmopressin acetate or DDAVP Rhinal Tube.
An oral LD50 has not been established. An intravenous dose of 2 mg/kg in mice demonstrated no
effect.
6
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
Central Cranial Diabetes Insipidus: This drug is administered into the nose through a soft,
flexible plastic rhinal tube which has four graduation marks on it that measure 0.2, 0.15, 0.1 and
0.05 mL. DDAVP Rhinal Tube dosage must be determined for each individual patient and
adjusted according to the diurnal pattern of response. Response should be estimated by two
parameters: adequate duration of sleep and adequate, not excessive, water turnover. Patients with
nasal congestion and blockage have often responded well to intranasal DDAVP. The usual
dosage range in adults is 0.1 to 0.4 mL daily, either as a single dose or divided into two or three
doses. Most adults require 0.2 mL daily in two divided doses. The morning and evening doses
should be separately adjusted for an adequate diurnal rhythm of water turnover. For children
aged 3 months to 12 years, the usual dosage range is 0.05 to 0.3 mL daily, either as a single dose
or divided into two doses. About 1/4 to 1/3 of patients can be controlled by a single daily dose of
DDAVP administered intranasally. Fluid restriction should be observed. (See WARNINGS,
PRECAUTIONS, Pediatric Use and Geriatric Use.)
Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of
toxic reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY, Human Pharmacokinetics, CONTRAINDICATIONS, and
PRECAUTIONS, Geriatric Use.)
HOW SUPPLIED
DDAVP Rhinal Tube is available in a 2.5 mL bottle, packaged with two rhinal tube applicators
per carton (NDC 0075-2450-01). Also available in a 5.0 mL pump bottle with spray pump
delivering 50 doses of 10 mcg (NDC 0075-2452-01).
Store refrigerated 2 to 8°C (36 to 46°F). When traveling, closed bottles will maintain stability for
3 weeks when stored at controlled room temperature, 20 to 25°C (68 to 77°F).
Keep out of the reach of children.
MILITARY: DDAVP Rhinal Tube, 1 x 2.5 mL (NSN 6505-01-145-6338).
US Patent Nos. 5,500,413; 5,596,078; 5,674,850; 5,763,407
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rev. July 2007
©2007 sanofi-aventis U.S. LLC
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INSTRUCTION GUIDE
DDAVP®
Rhinal Tube
(desmopressin acetate)
Ensure that in children administration is under adult supervision in order to control the
dose intake.
If you accidentally deliver/administer too much of a dose, immediately telephone your doctor or
a certified Regional Poison Center for advice. Possible signs of overdose may include confusion,
drowsiness, continuing headache, problems with passing urine and rapid weight gain due to fluid
retention.
1. Pull plastic tag on neck of bottle.
2. Break security seal and remove plastic cap.
3. Twist off the small knurled seal from the dropper. Use the same seal reversed to prevent
subsequent leakage, especially if the bottle is not stored upright.
9
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10
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4. The drug is administered by a soft, flexible, plastic rhinal tube which has dose marks at 0.2,
0.15, 0.1 and 0.05 mL. Take the arrow-marked part of the tube in one hand and place the
fingers of the other hand around the cylindrical part of the closure. Insert the top of the
dropper in a downward position into the arrow-marked end of the tube and squeeze the
dropper until the solution has reached the desired calibration mark. The dose is measured
from the arrow-marked end of the tube to the appropriate calibration. Disconnect the tube
from the bottle by withdrawing the bottle quickly downwards. In order to prevent air bubbles
from forming in the tube, maintain constant pressure on the dropper. If difficulty is
experienced in filling the tube, a diabetic or tuberculin syringe may be used to draw up the
dose and load the tube.
5. Hold the tube with the fingers approximately ¾ inch from the end and insert into a nostril
until the tips of the fingers reach the nostril.
11
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6. Put the other end of the tube into the mouth. Hold the breath, tilt the head back and then blow
with a short, strong puff through the tube so that the solution reaches the right place in the
nasal cavity. Through this procedure, medication is limited to the nasal cavity and the
preparation does not pass down into the throat.
In very young patients, it may be necessary for an adult to blow the solution into the child’s
nose. In such cases, the tube will not need to be put into the nose as far as in the older child
or adult. The tube should be placed in the nose gently just far enough so that the solution
does not run out. A baby must be held firmly and securely.
7. After use, reseal dropper tip and close the bottle with the plastic cap. Wash the tube in
water and shake thoroughly, until no more water is left. The tube can then be used for the
next application.
IMPORTANT:
Replace Knurled Seal
12
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Store refrigerated 2 to 8°C (36 to 46°F). When traveling, closed bottles will maintain stability for
3 weeks when stored at controlled room temperature, 20 to 25°C (68 to 77°F).
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Rev. July 2007
©2007 sanofi-aventis U.S. LLC
13
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DDAVPP® Injection
(desmopressin acetate)
4 mcg/mL
Rx only
DESCRIPTION
DDAVP® Injection (desmopressin acetate) 4 mcg/mL is a synthetic analogue of the natural pituitary
hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. It
is chemically defined as follows:
Mol. Wt. 1183.34
Empirical Formula: C46H64N14O12S2•C2H4O2•3H2O
1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
DDAVP Injection 4 mcg/mL is provided as a sterile, aqueous solution for injection.
Each mL provides:
Desmopressin acetate 4.0 mcg
Sodium chloride
9.0 mg
Hydrochloric acid to adjust pH to 4
The 10 mL vial contains chlorobutanol as a preservative (5.0 mg/mL).
CLINICAL PHARMACOLOGY
DDAVP Injection 4 mcg/mL contains as active substance, desmopressin acetate, a synthetic
analogue of the natural hormone arginine vasopressin. One mL (4 mcg) of DDAVP (desmopressin
acetate) solution has an antidiuretic activity of about 16 IU; 1 mcg of DDAVP is equivalent to 4 IU.
DDAVP has been shown to be more potent than arginine vasopressin in increasing plasma levels of
factor VIII activity in patients with hemophilia and von Willebrand’s disease Type I.
Dose-response studies were performed in healthy persons, using doses of 0.1 to 0.4 mcg/kg body
weight, infused over a 10-minute period. Maximal dose response occurred at 0.3 to 0.4 mcg/kg. The
response to DDAVP of factor VIII activity and plasminogen activator is dose-related, with maximal
plasma levels of 300 to 400 percent of initial concentrations obtained after infusion of 0.4 mcg/kg
body weight. The increase is rapid and evident within 30 minutes, reaching a maximum at a point
ranging from 90 minutes to two hours. The factor VIII related antigen and ristocetin cofactor activity
were also increased to a smaller degree, but still are dose-dependent.
1
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1. The biphasic half-lives of DDAVP were 7.8 and 75.5 minutes for the fast and slow phases,
respectively, compared with 2.5 and 14.5 minutes for lysine vasopressin, another form of the
hormone. As a result, DDAVP provides a prompt onset of antidiuretic action with a long duration
after each administration.
2. The change in structure of arginine vasopressin to DDAVP has resulted in a decreased vasopressor
action and decreased actions on visceral smooth muscle relative to the enhanced antidiuretic
activity, so that clinically effective antidiuretic doses are usually below threshold levels for effects
on vascular or visceral smooth muscle.
3. When administered by injection, DDAVP has an antidiuretic effect about ten times that of an
equivalent dose administered intranasally.
4. The bioavailability of the subcutaneous route of administration was determined qualitatively using
urine output data. The exact fraction of drug absorbed by that route of administration has not been
quantitatively determined.
5. The percentage increase of factor VIII levels in patients with mild hemophilia A and von
Willebrand’s disease was not significantly different from that observed in normal healthy
individuals when treated with 0.3 mcg/kg of DDAVP infused over 10 minutes.
6. Plasminogen activator activity increases rapidly after DDAVP infusion, but there has been no
clinically significant fibrinolysis in patients treated with DDAVP.
7. The effect of repeated DDAVP administration when doses were given every 12 to 24 hours has
generally shown a gradual diminution of the factor VIII activity increase noted with a single dose.
The initial response is reproducible in any particular patient if there are 2 or 3 days between
administrations.
Human Pharmacokinetics: DDAVP is mainly excreted in the urine. A pharmacokinetic study
conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment (n=24,
6 subjects in each group) receiving single dose desmopressin acetate (2mcg) injection demonstrated a
difference in DDAVP terminal half-life. Terminal half-life significantly increased from 3 hours in
normal healthy patients to 9 hours in patients with severe renal impairment. (See
CONTRAINDICATIONS.)
INDICATIONS AND USAGE
Hemophilia A: DDAVP Injection 4 mcg/mL is indicated for patients with hemophilia A with factor
VIII coagulant activity levels greater than 5%.
DDAVP will often maintain hemostasis in patients with hemophilia A during surgical procedures and
postoperatively when administered 30 minutes prior to scheduled procedure.
DDAVP will also stop bleeding in hemophilia A patients with episodes of spontaneous or trauma-
induced injuries such as hemarthroses, intramuscular hematomas or mucosal bleeding.
2
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DDAVP is not indicated for the treatment of hemophilia A with factor VIII coagulant activity
levels equal to or less than 5%, or for the treatment of hemophilia B, or in patients who have
factor VIII antibodies.
In certain clinical situations, it may be justified to try DDAVP in patients with factor VIII levels
between 2% to 5%; however, these patients should be carefully monitored.
von Willebrand’s Disease (Type I): DDAVP Injection 4 mcg/mL is indicated for patients with mild
to moderate classic von Willebrand’s disease (Type I) with factor VIII levels greater than 5%.
DDAVP will often maintain hemostasis in patients with mild to moderate von Willebrand’s disease
during surgical procedures and postoperatively when administered 30 minutes prior to the scheduled
procedure.
DDAVP will usually stop bleeding in mild to moderate von Willebrand’s patients with episodes of
spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematomas or mucosal
bleeding.
Those von Willebrand’s disease patients who are least likely to respond are those with severe
homozygous von Willebrand’s disease with factor VIII coagulant activity and factor VIII von
Willebrand factor antigen levels less than 1%. Other patients may respond in a variable fashion
depending on the type of molecular defect they have. Bleeding time and factor VIII coagulant activity,
ristocetin cofactor activity, and von Willebrand factor antigen should be checked during
administration of DDAVP to ensure that adequate levels are being achieved.
DDAVP is not indicated for the treatment of severe classic von Willebrand’s disease (Type I) and
when there is evidence of an abnormal molecular form of factor VIII antigen. (See WARNINGS.)
Diabetes Insipidus: DDAVP Injection 4 mcg/mL is indicated as antidiuretic replacement therapy in
the management of central (cranial) diabetes insipidus and for the management of the temporary
polyuria and polydipsia following head trauma or surgery in the pituitary region. DDAVP is
ineffective for the treatment of nephrogenic diabetes insipidus.
DDAVP is also available as an intranasal preparation. However, this means of delivery can be
compromised by a variety of factors that can make nasal insufflation ineffective or inappropriate.
These include poor intranasal absorption, nasal congestion and blockage, nasal discharge,
atrophy of nasal mucosa, and severe atrophic rhinitis. Intranasal delivery may be inappropriate
where there is an impaired level of consciousness. In addition, cranial surgical procedures, such
as transsphenoidal hypophysectomy, create situations where an alternative route of
administration is needed as in cases of nasal packing or recovery from surgery.
CONTRAINDICATIONS
3
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DDAVP Injection 4 mcg/mL is contraindicated in individuals with known hypersensitivity to
desmopressin acetate or to any of the components of DDAVP Injection 4 mcg/mL.
DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as a
creatinine clearance below 50ml/min).
DDAVP is contraindicated in patients with hyponatremia or a history of hyponatremia.
WARNINGS
1. Very rare cases of hyponatremia have been reported from world-wide postmarketing
experience in patients treated with DDAVP (desmopressin acetate). DDAVP is a potent
antidiuretic which, when administered, may lead to water intoxication and/or hyponatremia.
Unless properly diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction is
recommended and should be discussed with the patient and/or guardian. Careful medical
supervision is required.
2. When DDAVP Injection is administered to patients who do not have need of antidiuretic hormone
for its antidiuretic effect, in particular in pediatric and geriatric patients, fluid intake should be adjusted
downward to decrease the potential occurrence of water intoxication and hyponatremia. (See
PRECAUTIONS, Pediatric Use and Geriatric Use.) All patients receiving DDAVP therapy
should be observed for the following signs of symptoms associated with hyponatremia: headache,
nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy,
disorientation, depressed reflexes, loss of appetite, irritability, muscle weakness, muscle spasms
or cramps and abnormal mental status such as hallucinations, decreased consciousness and
confusion. Severe symptoms may include one or a combination of the following: seizure, coma
and/or respiratory arrest. Particular attention should be paid to the possibility of the rare
occurrence of an extreme decrease in plasma osmolality that may result in seizures which could
lead to coma.
3. DDAVP should not be used to treat patients with Type IIB von Willebrand’s disease since platelet
aggregation may be induced.
4. DDAVP should be used with caution in patients with habitual or psychogenic polydipsia who
may be more likely to drink excessive amounts of water, putting them at greater risk of
hyponatremia.
PRECAUTIONS
General: For injection use only.
4
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DDAVP Injection (desmopressin acetate) 4 mcg/mL has infrequently produced changes in blood
pressure causing either a slight elevation in blood pressure or a transient fall in blood pressure and a
compensatory increase in heart rate. The drug should be used with caution in patients with coronary
artery insufficiency and/or hypertensive cardiovascular disease.
DDAVP (desmopressin acetate) should be used with caution in patients with conditions associated
with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders, because
these patients are prone to hyponatremia.
There have been rare reports of thrombotic events following DDAVP Injection 4 mcg/mL in patients
predisposed to thrombus formation. No causality has been determined, however, the drug should be
used with caution in these patients.
Severe allergic reactions have been reported rarely. Anaphylaxis has been reported rarely with
intravenous and intranasal DDAVP, including isolated cases of fatal anaphylaxis with intravenous
DDAVP. It is not known whether antibodies to DDAVP Injection 4 mcg/mL are produced after
repeated injections.
Hemophilia A: Laboratory tests for assessing patient status include levels of factor VIII coagulant,
factor VIII antigen and factor VIII ristocetin cofactor (von Willebrand factor) as well as activated
partial thromboplastin time. Factor VIII coagulant activity should be determined before giving
DDAVP for hemostasis. If factor VIII coagulant activity is present at less than 5% of normal, DDAVP
should not be relied on.
von Willebrand’s Disease: Laboratory tests for assessing patient status include levels of factor VIII
coagulant activity, factor VIII ristocetin cofactor activity, and factor VIII von Willebrand factor
antigen. The skin bleeding time may be helpful in following these patients.
Diabetes Insipidus: Laboratory tests for monitoring the patient include urine volume and osmolality.
In some cases, plasma osmolality may be required.
Drug Interactions: Although the pressor activity of DDAVP is very low compared with the
antidiuretic activity, use of doses as large as 0.3 mcg/kg of DDAVP with other pressor agents should
be done only with careful patient monitoring. The concomitant administration of drugs that may
increase the risk of water intoxication with hyponatremia, (e.g. tricyclic antidepressants, selective
serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine and
carbamazepine) should be performed with caution.
DDAVP has been used with epsilon aminocaproic acid without adverse effects.
Carcinogenicity, Mutagenicity, Impairment of Fertility: Studies with DDAVP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
5
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Pregnancy Category B: Fertility studies have not been done. Teratology studies in rats and rabbits at
doses from 0.05 to 10 mcg/kg/day (approximately 0.1 times the maximum systemic human exposure
in rats and up to 38 times the maximum systemic human exposure in rabbits based on surface area,
mg/m
2) revealed no harm to the fetus due to DDAVP. There are, however, no adequate and well
controlled studies in pregnant women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only if clearly needed.
Several publications of desmopressin acetate’s use in the management of diabetes insipidus during
pregnancy are available; these include a few anecdotal reports of congenital anomalies and low birth
weight babies. However, no causal connection between these events and desmopressin acetate has
been established. A fifteen year, Swedish epidemiologic study of the use of desmopressin acetate in
pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that in the
general population; however, the statistical power of this study is low. As opposed to preparations
containing natural hormones, desmopressin acetate in antidiuretic doses has no uterotonic action and
the physician will have to weigh the therapeutic advantages against the possible risks in each case.
Nursing Mothers: There have been no controlled studies in nursing mothers. A single study in
postpartum women demonstrated a marked change in plasma, but little if any change in assayable
DDAVP in breast milk following an intranasal dose of 10 mcg. It is not known whether this drug is
excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised
when DDAVP is administered to a nursing woman.
Pediatric Use: Use in infants and pediatric patients will require careful fluid intake restriction to
prevent possible hyponatremia and water intoxication. Fluid restriction should be discussed with the
patient and/or guardian. (See WARNINGS.) DDAVP Injection 4 mcg/mL should not be used in
infants less than three months of age in the treatment of hemophilia A or von Willebrand’s disease;
safety and effectiveness in pediatric patients under 12 years of age with diabetes insipidus have not
been established.
Geriatric Use: Clinical studies of DDAVP Injection did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection should be cautious, usually starting at the low end of the dosing
range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function. DDAVP is contraindicated in patients with moderate to severe renal
impairment (defined as a creatinine clearance below 50ml/min). (See CLINICAL
PHARMACOLOGY, Human Pharmacokinetics and CONTRAINDICATIONS.)
6
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Use of DDAVP injection in geriatric patients will require careful fluid intake restrictions to prevent
possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient.
(See WARNINGS.)
ADVERSE REACTIONS
Infrequently, DDAVP has produced transient headache, nausea, mild abdominal cramps and vulval
pain. These symptoms disappeared with reduction in dosage. Occasionally, injection of DDAVP has
produced local erythema, swelling or burning pain. Occasional facial flushing has been reported with
the administration of DDAVP. DDAVP Injection has infrequently produced changes in blood
pressure causing either a slight elevation or a transient fall and a compensatory increase in heart rate.
Severe allergic reactions including anaphylaxis have been reported rarely with DDAVP Injection.
See WARNINGS for the possibility of water intoxication and hyponatremia.
Post Marketing: There have been rare reports of thrombotic events (acute cerebrovascular
thrombosis, acute myocardial infarction) following DDAVP Injection in patients predisposed to
thrombus formation, and rare reports of hyponatremic convulsions associated with concomitant
use with the following medications: oxybutinin and imipramine.
OVERDOSAGE
Signs of overdose may include confusion, drowsiness, continuing headache, problems with
passing urine and rapid weight gain due to fluid retention. (See WARNINGS.) In case of
overdosage, the dosage should be reduced, frequency of administration decreased, or the drug
withdrawn according to the severity of the condition.
There is no known specific antidote for desmopressin acetate or DDAVP Injection 4 mcg/mL.
An oral LD50 has not been established. An intravenous dose of 2 mg/kg in mice demonstrated no
effect.
DOSAGE AND ADMINISTRATION
Hemophilia A and von Willebrand’s Disease (Type I): DDAVP Injection 4 mcg/mL is
administered as an intravenous infusion at a dose of 0.3 mcg DDAVP/kg body weight diluted in
sterile physiological saline and infused slowly over 15 to 30 minutes. In adults and children weighing
more than 10 kg, 50 mL of diluent is recommended; in children weighing 10 kg or less, 10 mL of
diluent is recommended. Blood pressure and pulse should be monitored during infusion. If DDAVP
Injection 4 mcg/mL is used preoperatively, it should be administered 30 minutes prior to the
scheduled procedure.
7
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The necessity for repeat administration of DDAVP or use of any blood products for hemostasis should
be determined by laboratory response as well as the clinical condition of the patient. The tendency
toward tachyphylaxis (lessening of response) with repeated administration given more frequently than
every 48 hours should be considered in treating each patient.
Fluid restriction should be observed. (See WARNINGS, PRECAUTIONS, Pediatric Use and
Geriatric Use.)
Diabetes Insipidus: This formulation is administered subcutaneously or by direct intravenous
injection. DDAVP Injection 4 mcg/mL dosage must be determined for each patient and adjusted
according to the pattern of response. Response should be estimated by two parameters: adequate
duration of sleep and adequate, not excessive, water turnover.
The usual dosage range in adults is 0.5 mL (2.0 mcg) to 1 mL (4.0 mcg) daily, administered
intravenously or subcutaneously, usually in two divided doses. The morning and evening doses should
be separately adjusted for an adequate diurnal rhythm of water turnover. For patients who have been
controlled on intranasal DDAVP and who must be switched to the injection form, either because of
poor intranasal absorption or because of the need for surgery, the comparable antidiuretic dose of the
injection is about one-tenth the intranasal dose.
Fluid restriction should be observed. (See WARNINGS, PRECAUTIONS, Pediatric Use and
Geriatric Use.)
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection, and it may be
useful to monitor renal function. (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics,
CONTRAINDICATIONS, and PRECAUTIONS, Geriatric Use.)
Directions for use of One Point Cut (OPC) Ampules for DDAVP Injection:
1. Use aseptic technique to clean ampule. Gently tap the top of the ampule to assist the flow of
the solution from the upper portion of the ampule to the lower portion.
2. Locate the blue dot on the upper portion of the ampule. Below this dot is a small score on the
neck of the ampule. Hold the ampule with the blue dot facing away from you.
3. Cover the vial with an appropriate wipe. Apply pressure to the top and bottom portions of the
ampule to snap the ampule open away from you.
8
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HOW SUPPLIED
DDAVP Injection 4 mcg/mL is available as a sterile solution in cartons of ten 1 mL single-dose
ampules (NDC 0075-2451-01) and in 10 mL multiple-dose vials (NDC 0075-2451-53), each
containing 4.0 mcg DDAVP per mL.
Store refrigerated 2 to 8°C (36 to 46°F).
Keep out of the reach of children.
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
1.1
US Patents 5,500,413; 5,596,078; 5,763,407
Rev. July 2007
©2007 sanofi-aventis U.S. LLC
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DDAVP® Tablets
(desmopressin acetate)
Rx only
DESCRIPTION
DDAVP® Tablets (desmopressin acetate) are a synthetic analogue of the natural pituitary
hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water
conservation. It is chemically defined as follows:
Mol. Wt. 1183.34
Empirical Formula: C46H64N14O12S2 • C2H4O2 • 3H2O
1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
DDAVP Tablets contain either 0.1 or 0.2 mg desmopressin acetate. Inactive ingredients include:
lactose, potato starch, magnesium stearate and povidone.
CLINICAL PHARMACOLOGY
DDAVP Tablets contain as active substance, desmopressin acetate, a synthetic analogue of the
natural hormone arginine vasopressin.
Central Diabetes Insipidus: Dose response studies in patients with diabetes insipidus have
demonstrated that oral doses of 0.025 mg to 0.4 mg produced clinically significant antidiuretic
effects. In most patients, doses of 0.1 mg to 0.2 mg produced optimal antidiuretic effects lasting
up to eight hours. With doses of 0.4 mg, antidiuretic effects were observed for up to 12 hours;
measurements beyond 12 hours were not recorded. Increasing oral doses produced dose
dependent increases in the plasma levels of DDAVP (desmopressin acetate).
The plasma half-life of DDAVP followed a monoexponential time course with t1/2 values of 1.5
to 2.5 hours which was independent of dose.
The bioavailability of DDAVP oral tablets is about 5% compared to intranasal DDAVP, and
about 0.16% compared to intravenous DDAVP. The time to reach maximum plasma DDAVP
levels ranged from 0.9 to 1.5 hours following oral or intranasal administration, respectively.
Following administration of DDAVP Tablets, the onset of antidiuretic effect occurs at around 1
hour, and it reaches a maximum at about 4 to 7 hours based on the measurement of increased
urine osmolality.
The use of DDAVP Tablets in patients with an established diagnosis will result in a reduction in
urinary output with an accompanying increase in urine osmolality. These effects usually will
allow resumption of a more normal life style, with a decrease in urinary frequency and nocturia.
There are reports of an occasional change in response to the intranasal formulations of DDAVP
(DDAVP Nasal Spray and DDAVP Rhinal Tube). Usually, the change occurred over a period of
time greater than six months. This change may be due to decreased responsiveness, or to
shortened duration of effect. There is no evidence that this effect is due to the development of
binding antibodies, but may be due to a local inactivation of the peptide. No lessening of effect
was observed in the 46 patients who were treated with DDAVP Tablets for 12 to 44 months and
no serum antibodies to desmopressin were detected.
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The change in structure of arginine vasopressin to desmopressin acetate resulted in less
vasopressor activity and decreased action on visceral smooth muscle relative to enhanced
antidiuretic activity. Consequently, clinically effective antidiuretic doses are usually below the
threshold for effects on vascular or visceral smooth muscle. In the four long-term studies of
DDAVP Tablets, no increases in blood pressure in 46 patients receiving DDAVP Tablets for
periods of 12 to 44 months were reported.
In one study, the pharmacodynamic characteristics of DDAVP Tablets and intranasal
formulation were compared during an 8-hour dosing interval at steady state. The doses
administered to 36 hydrated (water loaded) healthy male adult volunteers every 8 hours were 0.1,
0.2, 0.4 mg orally and 0.01 mg intranasally by rhinal tube. The results are shown in the following
table:
Mean Changes from Baseline (SE) in Pharmacodynamic
Parameters in Normal Healthy Adult Volunteers
Treatment
Total Urine Volume
in mL
Maximum Urine
Osmolality in mOsm/kg
0.1 mg PO q8h
-3689.3 (149.6)
514.8 (21.9)
0.2 mg PO q8h
-4429.9 (149.6)
686.3 (21.9)
0.4 mg PO q8h
-4998.8 (149.6)
769.3 (21.9)
0.01 mg IN q8h
-4844.9 (149.6)
754.1 (21.9)
(SE) = Standard error of the mean
With respect to the mean values of total urine volume decrease and maximum urine osmolality
increase from baseline, the 90% confidence limits estimated that the 0.4 mg and 0.2 mg oral dose
produced between 95% and 110% and 84% to 99% of pharmacodynamic activity, respectively,
when compared to the 0.01 mg intranasal dose.
While both the 0.2 mg and 0.4 mg oral doses are considered pharmacodynamically similar to the
0.01 mg intranasal dose, the pharmacodynamic data on an inter-subject basis was highly variable
and, therefore, individual dosing is recommended.
In another study in diabetes insipidus patients, the pharmacodynamic characteristics of DDAVP
Tablets and intranasal formulations were compared over a 12-hour period. Ten fluid-controlled
patients under age 18 were administered tablet doses of 0.2 mg and 0.4 mg, and intranasal doses
of 0.01 mg and 0.02 mg.
Mean Peak Pharmacodynamic Parameters (SD) in Pediatric
and Adolescent Diabetes Insipidus Patients
Treatment
Urine Volume in
mL/min
Maximum Urine
Osmolality in mOsm/kg
0.01 mg IN
0.3 (0.15)
717.0 (224.63)
0.02 mg IN
0.3 (0.25)
761.8 (298.82)
0.2 mg PO
0.3 (0.12)
678.3 (147.91)
0.4 mg PO
0.2 (0.15)
787.2 (73.34)
(SD) = Standard Deviation
All four dose formulations (0.01 mg IN, 0.02 mg IN, 0.2 mg PO and 0.4 mg PO) have a similar,
pronounced pharmacodynamic effect on urine volume and urine osmolality. At two hours after
study drug administration, mean urine volume was 4 mL/min and urine osmolality was >500
mOsm/kg. Mean plasma osmolality remained relatively constant over the time course recorded
(0 to 12 hours). A statistical separation from baseline did not occur at any dose or time point. In
these patients, the 0.2 mg tablets and the 0.01 mg intranasal spray exhibited similar
pharmacodynamic profiles as did the 0.4 mg tablets and the 0.02 mg intranasal spray
formulation. In another study of adult diabetes insipidus patients previously controlled on
2
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DDAVP intranasal spray, after one week of self-titration from spray to tablets, patients’ diuresis
was controlled with 0.1 mg DDAVP Tablets three times a day.
Primary Nocturnal Enuresis: Two double-blind, randomized, placebo-controlled studies were
conducted in 340 patients with primary nocturnal enuresis. Patients were 5-17 years old, and
72% were males. A total of 329 patients were evaluated for efficacy. Patients were evaluated
over a two-week baseline period in which the average number of wet nights was 10 (range 4-14).
Patients were then randomized to receive 0.2, 0.4, or 0.6 mg of DDAVP or placebo. The pooled
results after two weeks are shown in the following table:
Response to DDAVP and Placebo at Two Weeks of Treatment
Mean (SE) Number of Wet Nights/2 Weeks
Placebo
(n = 85)
0.2 mg/day
(n = 79)
0.4 mg/day
(n = 82)
0.6 mg/day
(n = 83)
Baseline
10 (0.3)
11 (0.3)
10 (0.3)
10 (0.3)
Reduction from
Baseline
1 (0.3)
3 (0.4)
3 (0.4)
4 (0.4)
Percent Reduction
from Baseline
10%
27%
30%
40%
p-value vs placebo
----
<0.05
<0.05
<0.05
Patients treated with DDAVP Tablets showed a statistically significant reduction in the number
of wet nights compared to placebo-treated patients. A greater response was observed with
increasing doses up to 0.6 mg.
In a six month, open-label extension study, patients completing the placebo-controlled studies
were started on 0.2 mg/day DDAVP, and the dose was progressively increased until the optimal
response was achieved (maximum dose 0.6 mg/day). A total of 230 patients were evaluated for
efficacy; the average number of wet nights/2 weeks during the untreated baseline period was 10
(range 4-14), and the average duration (SD) of treatment was 4.2 (1.8) months. Twenty-five (25)
patients (11%) achieved a complete or near complete response (≤2 wet nights/2 weeks) and did
not require titration to the 0.6 mg/day dose. The majority of patients (198 of 230, 86%) were
titrated to the highest dose. When all dose groups were combined, 128 (56%) showed at least a
50% reduction from baseline in the number of wet nights/2 weeks, while 87 (38%) patients
achieved a complete or near complete response.
Human Pharmacokinetics: DDAVP is mainly excreted in the urine. A pharmacokinetic study
conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment
(n=24, 6 subjects in each group) receiving single dose desmopressin acetate (2mcg) injection
demonstrated a difference in DDAVP terminal half-life. Terminal half-life significantly
increased from 3 hours in normal healthy patients to 9 hours in patients with severe renal
impairment. (See CONTRAINDICATIONS.)
INDICATIONS AND USAGE
Central Diabetes Insipidus: DDAVP Tablets are indicated as antidiuretic replacement therapy
in the management of central diabetes insipidus and for the management of the temporary
polyuria and polydipsia following head trauma or surgery in the pituitary region. DDAVP is
ineffective for the treatment of nephrogenic diabetes insipidus.
Patients were selected for therapy based on the diagnosis by means of the water deprivation test,
the hypertonic saline infusion test, and/or response to antidiuretic hormone. Continued response
to DDAVP can be monitored by measuring urine volume and osmolality.
3
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Primary Nocturnal Enuresis: DDAVP Tablets are indicated for the management of primary
nocturnal enuresis. DDAVP may be used alone or as an adjunct to behavioral conditioning or
other non-pharmacologic intervention.
CONTRAINDICATIONS
DDAVP Tablets are contraindicated in individuals with known hypersensitivity to desmopressin
acetate or to any of the components of DDAVP Tablets.
DDAVP is contraindicated in patients with moderate to severe renal impairment (defined as a
creatinine clearance below 50ml/min).
DDAVP is contraindicated in patients with hyponatremia or a history of hyponatremia.
WARNINGS
1. Very rare cases of hyponatremia have been reported from world-wide postmarketing
experience in patients treated with DDAVP (desmopressin acetate). DDAVP is a potent
antidiuretic which, when administered, may lead to water intoxication and/or hyponatremia.
Unless properly diagnosed and treated hyponatremia can be fatal. Therefore, fluid restriction is
recommended and should be discussed with the patient and/or guardian. Careful medical
supervision is required.
2. When DDAVP Tablets are administered, in particular in pediatric and geriatric patients, fluid
intake should be adjusted downward to decrease the potential occurrence of water intoxication
and hyponatremia. (See PRECAUTIONS, Pediatric Use and Geriatric Use.) All patients
receiving DDAVP therapy should be observed for the following signs of symptoms associated
with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight gain,
restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss of appetite, irritability,
muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations,
decreased consciousness and confusion. Severe symptoms may include one or a combination of
the following: seizure, coma and/or respiratory arrest. Particular attention should be paid to the
possibility of the rare occurrence of an extreme decrease in plasma osmolality that may result in
seizures which could lead to coma.
3. DDAVP should be used with caution in patients with habitual or psychogenic polydipsia who
may be more likely to drink excessive amounts of water, putting them at greater risk of
hyponatremia.
PRECAUTIONS
General: Intranasal formulations of DDAVP at high doses and DDAVP Injection have
infrequently produced a slight elevation of blood pressure which disappears with a reduction of
dosage. Although this effect has not been observed when single oral doses up to 0.6 mg have
been administered, the drug should be used with caution in patients with coronary artery
insufficiency and/or hypertensive cardiovascular disease, because of a possible rise in blood
pressure.
DDAVP should be used with caution in patients with conditions associated with fluid and
electrolyte imbalance, such as cystic fibrosis, heart failure and renal disorders because these
patients are prone to hyponatremia.
Rare severe allergic reactions have been reported with DDAVP. Anaphylaxis has been reported
rarely with intravenous and intranasal administration of DDAVP but not with DDAVP Tablets.
Laboratory Tests: Central Diabetes Insipidus: Laboratory tests for monitoring the patient with
central diabetes insipidus or post-surgical or head trauma-related polyuria and polydipsia include
urine volume and osmolality. In some cases, measurements of plasma osmolality may be useful.
4
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Drug Interactions: Although the pressor activity of DDAVP is very low compared to its
antidiuretic activity, large doses of DDAVP Tablets should be used with other pressor agents
only with careful patient monitoring. The concomitant administration of drugs that may increase
the risk of water intoxication with hyponatremia, (e.g. tricyclic antidepressants, selective serotonin
re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine and carbamazepine)
should be performed with caution.
Carcinogenicity, Mutagenicity, Impairment of Fertility: Studies with DDAVP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Category B: Fertility studies have not been done. Teratology studies in rats and
rabbits at doses from 0.05 to 10 mcg/kg/day (approximately 0.1 times the maximum systemic
human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits
based on surface area, mg/m2) revealed no harm to the fetus due to DDAVP (desmopressin
acetate). There are, however, no adequate and well-controlled studies in pregnant women.
Because animal studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
Several publications where desmopressin acetate was used in the management of diabetes
insipidus during pregnancy are available; these include a few anecdotal reports of congenital
anomalies and low birth weight babies. However, no causal connection between these events and
desmopressin acetate has been established. A fifteen year Swedish epidemiologic study of the
use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth
defects to be no greater than that in the general population; however, the statistical power of this
study is low. As opposed to preparations containing natural hormones, desmopressin acetate in
antidiuretic doses has no uterotonic action and the physician will have to weigh the possible
therapeutic advantages against the possible risks in each case.
Nursing Mothers: There have been no controlled studies in nursing mothers. A single study in
postpartum women demonstrated a marked change in plasma, but little if any change in
assayable DDAVP in breast milk following an intranasal dose of 0.01 mg.
It is not known whether the drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when DDAVP is administered to nursing mothers.
Pediatric Use: Central Diabetes Insipidus: DDAVP Tablets (desmopressin acetate) have been
used safely in pediatric patients, age 4 years and older, with diabetes insipidus for periods up to
44 months. In younger pediatric patients the dose must be individually adjusted in order to
prevent an excessive decrease in plasma osmolality leading to hyponatremia and possible
convulsions; dosing should start at 0.05 mg (1/2 of the 0.1 mg tablet). Use of DDAVP Tablets in
pediatric patients requires careful fluid intake restrictions to prevent possible hyponatremia and
water intoxication. Fluid restriction should be discussed with the patient and/or guardian. (See
WARNINGS.)
Primary Nocturnal Enuresis: DDAVP Tablets have been safely used in pediatric patients age 6
years and older with primary nocturnal enuresis for up to 6 months. Some patients respond to a
dose of 0.2 mg; however, increasing responses are seen at doses of 0.4 mg and 0.6 mg. No
increase in the frequency or severity of adverse reactions or decrease in efficacy was seen with
an increased dose or duration. The dose should be individually adjusted to achieve the best
results. Treatment with desmopressin for primary nocturnal enuresis should be interrupted during
acute intercurrent illness characterized by fluid and/or electrolyte imbalance (e.g., systemic
infections, fever, recurrent vomiting or diarrhea) or under conditions of extremely hot weather,
vigorous exercise or other conditions associated with increased water intake.
Geriatric Use: Clinical studies of DDAVP Tablets did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
and younger patients. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function. DDAVP is contraindicated in patients with moderate to
severe renal impairment (defined as a creatinine clearance below 50ml/min). (See CLINICAL
PHARMACOLOGY, Human Pharmacokinetics and CONTRAINDICATIONS.)
Use of DDAVP Tablets in geriatric patients requires careful fluid intake restrictions to prevent
possible hyponatremia and water intoxication. Fluid restriction should be discussed with the patient.
(See WARNINGS.)
ADVERSE REACTIONS
Infrequently, large doses of the intranasal formulations of DDAVP and DDAVP Injection have
produced transient headache, nausea, flushing and mild abdominal cramps. These symptoms
have disappeared with reduction in dosage.
Central Diabetes Insipidus: In long-term clinical studies in which patients with diabetes
insipidus were followed for periods up to 44 months of DDAVP Tablet therapy, transient
increases in AST (SGOT) no higher than 1.5 times the upper limit of normal were occasionally
observed. Elevated AST (SGOT) returned to the normal range despite continued use of DDAVP
Tablets.
Primary Nocturnal Enuresis: The only adverse event occurring in ≥3% of patients in
controlled clinical trials with DDAVP Tablets that was probably, possibly, or remotely related
to study drug was headache (4% DDAVP, 3% placebo).
Other: The following adverse events have been reported; however their relationship to DDAVP
has not been established: abnormal thinking, diarrhea, and edema-weight gain.
See WARNINGS for the possibility of water intoxication and hyponatremia.
Post Marketing: There have been rare reports of hyponatremic convulsions associated with
concomitant use with the following medications: oxybutinin and imipramine.
OVERDOSAGE
Signs of overdose may include confusion, drowsiness, continuing headache, problems with
passing urine and rapid weight gain due to fluid retention. (See WARNINGS.) In case of
overdose, the dose should be reduced, frequency of administration decreased, or the drug
withdrawn according to the severity of the condition. There is no known specific antidote for
DDAVP. The patient should be observed and treated with appropriate symptomatic therapy.
An oral LD50 has not been established. Oral doses up to 0.2 mg/kg/day have been administered to
dogs and rats for 6 months without any significant drug-related toxicities reported. An
intravenous dose of 2 mg/kg in mice demonstrated no effect.
DOSAGE AND ADMINISTRATION
Central Diabetes Insipidus: The dosage of DDAVP Tablets must be determined for each
individual patient and adjusted according to the diurnal pattern of response. Response should be
estimated by two parameters: adequate duration of sleep and adequate, not excessive, water
turnover. Patients previously on intranasal DDAVP therapy should begin tablet therapy twelve
hours after the last intranasal dose. During the initial dose titration period, patients should be
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
observed closely and appropriate safety parameters measured to assure adequate response.
Patients should be monitored at regular intervals during the course of DDAVP Tablet therapy to
assure adequate antidiuretic response. Modifications in dosage regimen should be implemented
as necessary to assure adequate water turnover. Fluid restriction should be observed. (See
WARNINGS, PRECAUTIONS, Pediatric Use and Geriatric Use.)
Adults and Children: It is recommended that patients be started on doses of 0.05 mg (1/2 of the
0.1 mg tablet) two times a day and individually adjusted to their optimum therapeutic dose. Most
patients in clinical trials found that the optimal dosage range is 0.1 mg to 0.8 mg daily,
administered in divided doses. Each dose should be separately adjusted for an adequate diurnal
rhythm of water turnover. Total daily dosage should be increased or decreased in the range of 0.1
mg to 1.2 mg divided into two or three daily doses as needed to obtain adequate antidiuresis. See
Pediatric Use subsection for special considerations when administering desmopressin acetate to
pediatric diabetes insipidus patients.
Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of
toxic reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY, Human Pharmacokinetics, CONTRAINDICATIONS, and
PRECAUTIONS, Geriatric Use.)
Primary Nocturnal Enuresis: The dosage of DDAVP Tablets must be determined for each
individual patient and adjusted according to response. Patients previously on intranasal DDAVP
therapy can begin tablet therapy the night following (24 hours after) the last intranasal dose. The
recommended initial dose for patients age 6 years and older is 0.2 mg at bedtime. The dose may
be titrated up to 0.6 mg to achieve the desired response. Fluid restriction should be observed, and
fluid intake should be limited to a minimum from 1 hour before desmopressin administration,
until the next morning, or at least 8 hours after administration. (See WARNINGS,
PRECAUTIONS, Pediatric Use and Geriatric Use.)
HOW SUPPLIED
Strength
Size
NDC 0075-
Color
Markings
0.1 mg
Bottle
of 100
0016-00
White
0.2 mg
Bottle
of 100
0026-00
White
Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP]. Avoid exposure to
excessive heat or light.
This product should be dispensed in a container with a child-resistant cap.
Keep out of the reach of children.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
U.S. Patent Nos. 5,500,413; 5,596,078; 5,674,850; 5,047,398; 5,763,407
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807 USA
Rev. July 2007
©2007 sanofi-aventis U.S. LLC
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:25.046545
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017922s038,018938s027,019955s013lbl.pdf', 'application_number': 17922, 'submission_type': 'SUPPL ', 'submission_number': 38}
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11,093
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1
ORTHO-NOVUM® Tablets (norethindrone/ethinyl estradiol)
and MODICON® Tablets (norethindrone/ethinyl estradiol)
WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING
Cigarette smoking increases the risk of serious cardiovascular events from combination oral
contraceptive use. This risk increases with age, particularly in women over 35 years of age, and
with the number of cigarettes smoked. For this reason, combination oral contraceptives,
including ORTHO-NOVUM and MODICON, should not be used by women who are over
35 years of age and smoke.
Patients should be counseled that this product does not protect against HIV infection
(AIDS) and other sexually transmitted diseases.
COMBINED ORAL CONTRACEPTIVES
Each of the following products is a combined oral contraceptive containing the progestational
compound norethindrone and the estrogenic compound ethinyl estradiol.
ORTHO-NOVUM® 7/7/7 Tablets:
Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive
ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each light peach
tablet contains 0.75 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients
include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each
peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive
ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn
starch. Each green tablet contains only inert ingredients, as follows: D&C Yellow
No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate,
microcrystalline cellulose and pregelatinized corn starch.
ORTHO-NOVUM® 1/35 Tablets:
Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive
ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn
starch. Each green tablet contains only inert ingredients, as listed under green tablets in
ORTHO-NOVUM® 7/7/7.
MODICON® Tablets:
Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive
ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each green tablet
contains only inert ingredients, as listed under green tablets in ORTHO-NOVUM® 7/7/7.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one, and
for ethinyl estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their structural
formulas are as follows:
Norethindrone
Ethinyl estradiol
CLINICAL PHARMACOLOGY
Combined Oral Contraceptives
Combined oral contraceptives act by suppression of gonadotropins. Although the primary
mechanism of this action is inhibition of ovulation, other alterations include changes in the
cervical mucus (which increase the difficulty of sperm entry into the uterus) and the
endometrium (which reduce the likelihood of implantation).
INDICATIONS AND USAGE
ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® Tablets are indicated for
the prevention of pregnancy in women who elect to use this product as a method of
contraception.
Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for
users of combined oral contraceptives and other methods of contraception. The efficacy of these
contraceptive methods, except sterilization, the IUD, and the NORPLANT® System depends
upon the reliability with which they are used. Correct and consistent use of methods can result in
lower failure rates.
Table 1:
Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical
Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at
the End of the First Year. United States.
% of Women Experiencing an Unintended
Pregnancy within the First Year of Use
% of Women Continuing Use
at One Year*
Method
(1)
Typical Use†
(2)
Perfect Use‡
(3)
(4)
Chance#
85
85
SpermicidesÞ
26
6
40
Periodic abstinence
25
63
Calendar
9
Ovulation Method
3
Sympto-Thermalß
2
Post-Ovulation
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Table 1:
Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical
Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at
the End of the First Year. United States.
% of Women Experiencing an Unintended
Pregnancy within the First Year of Use
% of Women Continuing Use
at One Year*
Method
(1)
Typical Use†
(2)
Perfect Use‡
(3)
(4)
Capà
Parous Women
40
26
42
Nulliparous Women
20
9
56
Sponge
Parous Women
40
20
42
Nulliparous Women
20
9
56
Diaphragmà
20
6
56
Withdrawal
19
4
Condomè
Female (Reality®)
21
5
56
Male
14
3
61
Pill
5
71
Progestin Only
0.5
Combined
0.1
IUD
Progesterone T
2.0
1.5
81
Copper T380A
0.8
0.6
78
LNg 20
0.1
0.1
81
Depo-Provera®
0.3
0.3
70
Norplant® and Norplant-2®
0.05
0.05
88
Female Sterilization
0.5
0.5
100
Male Sterilization
0.15
0.10
100
Adapted from Hatcher et al., 1998, Ref. #1.
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of
pregnancy by at least 75%.§
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.¶
Source: Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D,
Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Table 1:
Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical
Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at
the End of the First Year. United States.
% of Women Experiencing an Unintended
Pregnancy within the First Year of Use
% of Women Continuing Use
at One Year*
Method
(1)
Typical Use†
(2)
Perfect Use‡
(3)
(4)
* Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
† Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who
experience an accidental pregnancy during the first year if they do not stop use for any other reason.
‡ Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both
consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do
not stop use for any other reason.
§ The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after
the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be
safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills),
Nordette® or Levlen® (1 dose is 2 light-orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-
Levlen® (1 dose is 4 yellow pills).
¶ However, to maintain effective protection against pregnancy, another method of contraception must be used as
soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or
the baby reaches six months of age.
# The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is
not used and from women who cease using contraception in order to become pregnant. Among such populations,
about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent
who would become pregnant within one year among women now relying on reversible methods of contraception
if they abandoned contraception altogether.
Þ Foams, creams, gels, vaginal suppositories, and vaginal film.
ß Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in
the post-ovulatory phases.
à With spermicidal cream or jelly.
è Without spermicides.
ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35 and MODICON® have not been studied for
and are not indicated for use in emergency contraception.
CONTRAINDICATIONS
Oral contraceptives should not be used in women who currently have the following conditions:
• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Known thrombophilic conditions
• Cerebral vascular or coronary artery disease (current or history)
• Valvular heart disease with complications
• Persistent blood pressure values of ≥ 160 mm Hg systolic or ≥ 100 mg Hg diastolic96
• Diabetes with vascular involvement
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• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Known or suspected carcinoma of the breast
• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Acute or chronic hepatocellular disease with abnormal liver function
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Hypersensitivity to any component of this product
WARNINGS
Cigarette smoking increases the risk of serious cardiovascular events from combination
oral contraceptive use. This risk increases with age, particularly in women over 35 years of
age, and with the number of cigarettes smoked. For this reason, combination oral
contraceptives, including ORTHO-NOVUM and MODICON, should not be used by
women who are over 35 years of age and smoke.
The use of oral contraceptives is associated with increased risks of several serious conditions
including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder
disease, although the risk of serious morbidity or mortality is very small in healthy women
without underlying risk factors. The risk of morbidity and mortality increases significantly in the
presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and
diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information
relating to these risks.
The information contained in this package insert is principally based on studies carried out in
patients who used oral contraceptives with higher formulations of estrogens and progestogens
than those in common use today. The effect of long-term use of the oral contraceptives with
lower formulations of both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retrospective or case
control studies and prospective or cohort studies. Case control studies provide a measure of the
relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive
users to that among nonusers. The relative risk does not provide information on the actual
clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is
the difference in the incidence of disease between oral contraceptive users and nonusers. The
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attributable risk does provide information about the actual occurrence of a disease in the
population (adapted from refs. 2 and 3 with the author’s permission). For further information, the
reader is referred to a text on epidemiological methods.
1. Thromboembolic Disorders and Other Vascular Problems
a. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk
is primarily in smokers or women with other underlying risk factors for coronary artery disease
such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of
heart attack for current oral contraceptive users has been estimated to be two to six.4–10 The risk
is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially
to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking
accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease
have been shown to increase substantially in smokers, especially in those 35 years of age and
older, and in nonsmokers over the age of 40 among women who use oral contraceptives.
(See Figure 1).
Figure 1.
Circulatory Disease Mortality Rates per 100,000 Women-Years by Age, Smoking Status and Oral
Contraceptive Use
(Adapted from P.M. Layde and V. Beral, ref. #12.)
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension,
diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to
decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of
hyperinsulinism.14–18 Oral contraceptives have been shown to increase blood pressure among
users (see Section 9 in WARNINGS). Similar effects on risk factors have been associated with
an increased risk of heart disease. Oral contraceptives must be used with caution in women with
cardiovascular disease risk factors.
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b. Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the use of oral
contraceptives is well established. Case control studies have found the relative risk of users
compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for
deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing
conditions for venous thromboembolic disease.2,3,19–24 Cohort studies have shown the relative
risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring
hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives
gradually disappears after combined oral contraceptive (COC) use is stopped.2 VTE risk is
highest in the first year of use and when restarting hormonal contraception after a break of four
weeks or longer.
A two- to four-fold increase in relative risk of post-operative thromboembolic complications has
been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in
women who have predisposing conditions is twice that of women without such medical
conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to
and for two weeks after elective surgery of a type associated with an increase in risk of
thromboembolism and during and following prolonged immobilization. Since the immediate
postpartum period is also associated with an increased risk of thromboembolism, oral
contraceptives should be started no earlier than four weeks after delivery in women who elect not
to breastfeed.
c. Cerebrovascular diseases
Oral contraceptives have been shown to increase both the relative and attributable risks of
cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is
greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found
to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted
to increase the risk of stroke.27–29
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for
normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic
stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who
did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for
normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also
greater in older women.3
d. Dose-related risk of vascular disease from oral contraceptives
A positive association has been observed between the amount of estrogen and progestogen in
oral contraceptives and the risk of vascular disease.31–33 A decline in serum high density
lipoproteins (HDL) has been reported with many progestational agents.14–16 A decline in serum
high density lipoproteins has been associated with an increased incidence of ischemic heart
disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive
depends on a balance achieved between doses of estrogen and progestogen and the activity of the
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8
progestogen used in the contraceptives. The activity and amount of both hormones should be
considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of
therapeutics. For any particular estrogen/progestogen combination, the dosage regimen
prescribed should be one which contains the least amount of estrogen and progestogen that is
compatible with a low failure rate and the needs of the individual patient. New acceptors of oral
contraceptive agents should be started on preparations containing the lowest estrogen content
which is judged appropriate for the individual patient.
e. Persistence of risk of vascular disease
There are two studies which have shown persistence of risk of vascular disease for ever-users of
oral contraceptives. In a study in the United States, the risk of developing myocardial infarction
after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years who
had used oral contraceptives for five or more years, but this increased risk was not demonstrated
in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular
disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess
risk was very small.34 However, both studies were performed with oral contraceptive
formulations containing 50 micrograms or higher of estrogens.
2. Estimates of Mortality From Contraceptive Use
One study gathered data from a variety of sources which have estimated the mortality rate
associated with different methods of contraception at different ages (Table 2). These estimates
include the combined risk of death associated with contraceptive methods plus the risk
attributable to pregnancy in the event of method failure. Each method of contraception has its
specific benefits and risks. The study concluded that with the exception of oral contraceptive
users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all
methods of birth control is low and below that associated with childbirth. The observation of an
increase in risk of mortality with age for oral contraceptive users is based on data gathered in the
1970’s.35 Current clinical recommendation involves the use of lower estrogen dose formulations
and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs
Advisory Committee was asked to review the use of oral contraceptives in women 40 years of
age and over. The Committee concluded that although cardiovascular disease risks may be
increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the
newer low-dose formulations), there are also greater potential health risks associated with
pregnancy in older women and with the alternative surgical and medical procedures which may
be necessary if such women do not have access to effective and acceptable means of
contraception. The Committee recommended that the benefits of low-dose oral contraceptive use
by healthy non-smoking women over 40 may outweigh the possible risks.
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9
Of course, older women, as all women who take oral contraceptives, should take an oral
contraceptive which contains the least amount of estrogen and progestogen that is compatible
with a low failure rate and individual patient needs.
Table 2:
ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS
ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN,
BY FERTILITY CONTROL METHOD ACCORDING TO AGE
Method of control and outcome
15–19
20–24
25–29
30–34
35–39
40–44
No fertility-control methods*
7.0
7.4
9.1
14.8
25.7
28.2
Oral contraceptives non-smoker†
0.3
0.5
0.9
1.9
13.8
31.6
Oral contraceptives smoker†
2.2
3.4
6.6
13.5
51.1
117.2
IUD†
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
Adapted from H.W. Ory, ref. #35.
* Deaths are birth-related.
† Deaths are method-related.
3. Carcinoma of the Reproductive Organs and Breasts
Numerous epidemiological studies have been performed on the incidence of breast, endometrial,
ovarian and cervical cancer in women using oral contraceptives. The risk of having breast cancer
diagnosed may be slightly increased among current and recent users of COCs. However, this
excess risk appears to decrease over time after COC discontinuation and by 10 years after
cessation the increased risk disappears. Some studies report an increased risk with duration of
use while other studies do not and no consistent relationships have been found with dose or type
of steroid. Some studies have found a small increase in risk for women who first use COCs
before age 20. Most studies show a similar pattern of risk with COC use regardless of a woman’s
reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than
in nonusers.
Women who currently have or have had breast cancer should not use oral contraceptives because
breast cancer is usually a hormonally-sensitive tumor.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk
of cervical intraepithelial neoplasia in some populations of women.45–48 However, there
continues to be controversy about the extent to which such findings may be due to differences in
sexual behavior and other factors.
In spite of many studies of the relationship between oral contraceptive use and breast and
cervical cancers, a cause-and-effect relationship has not been established.
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4. Hepatic Neoplasia
Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of
benign tumors is rare in the United States. Indirect calculations have estimated the attributable
risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years
of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas
may cause death through intra-abdominal hemorrhage.50,51
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in
long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the
U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users
approaches less than one per million users.
5. Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the use of oral
contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or
complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions.
Appropriate diagnostic and therapeutic measures should be undertaken immediately.
6. Oral Contraceptive Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who
have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not
indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction
defects are concerned,55,56,58,59 when taken inadvertently during early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a
test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened
or habitual abortion.
It is recommended that for any patient who has missed two consecutive periods, pregnancy
should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility of
pregnancy should be considered at the time of the first missed period. Oral contraceptive use
should be discontinued if pregnancy is confirmed.
7. Gallbladder Disease
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of
oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative
risk of developing gallbladder disease among oral contraceptive users may be minimal.62–64 The
recent findings of minimal risk may be related to the use of oral contraceptive formulations
containing lower hormonal doses of estrogens and progestogens.
8. Carbohydrate and Lipid Metabolic Effects
Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant
percentage of users.17 This effect has been shown to be directly related to estrogen dose.65
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Progestogens increase insulin secretion and create insulin resistance, this effect varying with
different progestational agents.17,66 However, in the non-diabetic woman, oral contraceptives
appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects,
prediabetic and diabetic women in particular should be carefully monitored while taking oral
contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As
discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein
levels have been reported in oral contraceptive users.
9. Elevated Blood Pressure
Women with significant hypertension should not be started on hormonal contraception.92 An
increase in blood pressure has been reported in women taking oral contraceptives68 and this
increase is more likely in older oral contraceptive users69 and with extended duration of use.61
Data from the Royal College of General Practitioners12 and subsequent randomized trials have
shown that the incidence of hypertension increases with increasing progestational activity.
Women with a history of hypertension or hypertension-related diseases, or renal disease70 should
be encouraged to use another method of contraception. If these women elect to use oral
contraceptives, they should be monitored closely and if a clinically significant persistent
elevation of blood pressure (BP) occurs (≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic) and
cannot be adequately controlled, oral contraceptives should be discontinued. In general, women
who develop hypertension during hormonal contraceptive therapy should be switched to a
non-hormonal contraceptive. If other contraceptive methods are not suitable, hormonal
contraceptive therapy may continue combined with antihypertensive therapy. Regular monitoring
of BP throughout hormonal contraceptive therapy is recommended.96 For most women, elevated
blood pressure will return to normal after stopping oral contraceptives, and there is no difference
in the occurrence of hypertension between former and never users.68–71
10. Headache
The onset or exacerbation of migraine or development of headache with a new pattern which is
recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of
the cause.
11. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral
contraceptives, especially during the first three months of use. Nonhormonal causes should be
considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the
event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology
has been excluded, time or a change to another formulation may solve the problem. In the event
of amenorrhea, pregnancy should be ruled out.
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Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a
condition was preexistent.
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
1. General
Patients should be counseled that this product does not protect against HIV infection
(AIDS) and other sexually transmitted diseases.
2. Physical Examination and Follow-Up
It is good medical practice for all women to have annual history and physical examinations,
including women using oral contraceptives. The physical examination, however, may be deferred
until after initiation of oral contraceptives if requested by the woman and judged appropriate by
the clinician. The physical examination should include special reference to blood pressure,
breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In
case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures
should be conducted to rule out malignancy. Women with a strong family history of breast
cancer or who have breast nodules should be monitored with particular care.
3. Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if they elect to use
oral contraceptives. Some progestogens may elevate LDL levels and may render the control of
hyperlipidemias more difficult.
4. Liver Function
If jaundice develops in any woman receiving such drugs, the medication should be discontinued.
Steroid hormones may be poorly metabolized in patients with impaired liver function.
5. Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with
caution, and only with careful monitoring, in patients with conditions which might be aggravated
by fluid retention.
6. Emotional Disorders
Women with a history of depression should be carefully observed and the drug discontinued if
depression recurs to a serious degree.
7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed
by an ophthalmologist.
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8. Drug Interactions
Consult the labeling of concurrently-used drugs to obtain further information about interactions
with hormonal contraceptives or the potential for enzyme alterations.
Effects of Other Drugs on Combined Hormonal Contraceptives
Substances decreasing the plasma concentrations of COCs and potentially diminishing
the efficacy of COCs
Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4
(CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the
effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that
may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates,
carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate,
rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between
hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive
failure. Counsel women to use an alternative method of contraception or a back-up method when
enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after
discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the plasma concentrations of COCs
Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC
values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma
EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as
itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma
hormone concentrations.
Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and
non-nucleoside reverse transcriptase inhibitors
Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or
progestin have been noted in some cases of co-administration with HIV protease inhibitors
(decrease
[e.g.,
nelfinavir,
ritonavir,
darunavir/ritonavir,
(fos)amprenavir/ritonavir,
lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])
/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside
reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).
Colesevelam: Colesevelam, a bile acid sequestrant, given together with a combination oral
hormonal contraceptive, has been shown to significantly decrease the AUC of EE. A drug
interaction between the contraceptive and colesevelam was decreased when the two drug
products were given 4 hours apart.
Effects of Combined Hormonal Contraceptives on Other Drugs
COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine,
prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma
concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen,
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clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in
plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine
glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine
may be necessary.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone
because serum concentrations of thyroid-binding globulin increases with use of COCs.
9. Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by oral
contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased
norepinephrine-induced platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid
hormone, as measured by protein-bound iodine (PBI), T4 by column or by
radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4
concentration is unaltered.
c. Other binding proteins may be elevated in serum.
d. Sex-binding globulins are increased and result in elevated levels of total circulating sex
steroids and corticoids; however, free or biologically active levels remain unchanged.
e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be
affected.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical
significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.
10. Carcinogenesis
See WARNINGS.
11. Pregnancy
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS.
12. Nursing Mothers
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers
and a few adverse effects on the child have been reported, including jaundice and breast
enlargement. In addition, combined oral contraceptives given in the postpartum period may
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interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the
nursing mother should be advised not to use combined oral contraceptives but to use other forms
of contraception until she has completely weaned her child.
13. Pediatric Use
Safety and efficacy of ORTHO-NOVUM® Tablets and MODICON® Tablets have been
established in women of reproductive age. Safety and efficacy are expected to be the same for
postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product
before menarche is not indicated.
14. Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this
population.
INFORMATION FOR THE PATIENT
See Patient Labeling printed below.
ADVERSE REACTIONS
An increased risk of the following serious adverse reactions has been associated with the use of
oral contraceptives (See WARNINGS).
• Thrombophlebitis and venous thrombosis with or without embolism
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the use of oral
contraceptives:
• Mesenteric thrombosis
• Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral contraceptives and
are believed to be drug-related:
• Nausea
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• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Allergic reaction, including rash, urticaria, angioedema
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses
The following adverse reactions have been reported in users of oral contraceptives and a causal
association has been neither confirmed nor refuted:
• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
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• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Acne
• Changes in libido
• Colitis
• Budd-Chiari Syndrome
The following adverse reactions were also reported in clinical trials or during post-marketing
experience: Gastrointestinal Disorders: diarrhea, pancreatitis; Musculoskeletal and Connective
Tissue Disorders: muscle spasms, back pain; Reproductive System and Breast Disorders
vulvovaginal pruritus, pelvic pain, dysmenorrhea, vulvovaginal dryness; Psychiatric Disorders:
anxiety, mood swings, mood altered; Skin and Subcutaneous Tissue Disorders: pruritus,
photosensitivity reaction; General Disorders and Administration Site Conditions: edema
peripheral, fatigue, irritability, asthenia, malaise; Neoplasms Benign, Malignant, and Unspecified
(Including Cysts and Polyps): breast cancer, breast mass, breast neoplasm, cervix carcinoma;
Immune System Disorders: anaphylactic/anaphylactoid reaction; Hepatobiliary Disorders:
hepatitis, cholelithiasis.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of oral
contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may
occur in females.
NON-CONTRACEPTIVE HEALTH BENEFITS
The following non-contraceptive health benefits related to the use of combined oral
contraceptives are supported by epidemiological studies which largely utilized oral contraceptive
formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg
mestranol.73–78
Effects on menses:
• increased menstrual cycle regularity
• decreased blood loss and decreased incidence of iron deficiency anemia
This label may not be the latest approved by FDA.
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18
• decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
• decreased incidence of functional ovarian cysts
• decreased incidence of ectopic pregnancies
Other effects:
• decreased incidence of fibroadenomas and fibrocystic disease of the breast
• decreased incidence of acute pelvic inflammatory disease
• decreased incidence of endometrial cancer
• decreased incidence of ovarian cancer
DOSAGE AND ADMINISTRATION
To achieve maximum contraceptive effectiveness, ORTHO-NOVUM® Tablets and MODICON®
Tablets must be taken exactly as directed and at intervals not exceeding 24 hours.
ORTHO-NOVUM® Tablets and MODICON® Tablets are available with the DIALPAK® Tablet
Dispenser which is preset for a Sunday Start. Day 1 Start is also available.
Sunday Start
When taking ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON®, the first
"active" tablet should be taken on the first Sunday after menstruation begins. If the period begins
on Sunday, the first "active" tablet should be taken that day. Take one active tablet daily for
21 days followed by one green "reminder" tablet daily for 7 days. After 28 tablets have been
taken, a new course is started the next day (Sunday). For the first cycle of a Sunday Start
regimen, another method of contraception, such as a condom or spermicide, should be used until
after the first 7 consecutive days of administration.
If the patient misses one (1) "active" tablet in Weeks 1, 2, or 3, the tablet should be taken as soon
as she remembers. If the patient misses two (2) "active" tablets in Week 1 or Week 2, the patient
should take two (2) tablets the day she remembers and two (2) tablets the next day; and then
continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed
to use a back-up method of birth control, such as a condom or spermicide, if she has sex in the
seven (7) days after missing pills. If the patient misses two (2) "active" tablets in the third week
or misses three (3) or more "active" tablets in a row, the patient should continue taking one tablet
every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a
new pack that same day. The patient should be instructed to use a back-up method of birth
control if she has sex in the seven (7) days after missing pills.
Complete instructions to facilitate patient counseling on proper pill usage may be found in the
Detailed Patient Labeling ("How to Take the Pill" section).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Day 1 Start
The dosage of ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON®, for the
initial cycle of therapy, is one "active" tablet administered daily from the 1st through the 21st day
of the menstrual cycle, counting the first day of menstrual flow as "Day 1" followed by one
green "reminder" tablet daily for 7 days. Tablets are taken without interruption for 28 days. After
28 tablets have been taken, a new course is started the next day.
If the patient misses one (1) "active" tablet in Weeks 1, 2, or 3, the tablet should be taken as soon
as she remembers. If the patient misses two (2) "active" tablets in Week 1 or Week 2, the patient
should take two (2) tablets the day she remembers and two (2) tablets the next day; and then
continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed
to use a back-up method of birth control, such as a condom or spermicide, if she has sex in the
seven (7) days after missing pills. If the patient misses two (2) "active" tablets in the third week
or misses three (3) or more "active" tablets in a row, the patient should throw out the rest of the
pack and start a new pack that same day. The patient should be instructed to use a back-up
method of birth control if she has sex in the seven (7) days after missing pills.
Complete instructions to facilitate patient counseling on proper pill usage may be found in the
Detailed Patient Labeling ("How to Take the Pill" section).
The use of ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® for
contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. When
the tablets are administered during the postpartum period, the increased risk of thromboembolic
disease
associated
with
the
postpartum
period
must
be
considered.
(See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also
PRECAUTIONS: Nursing Mothers.) The possibility of ovulation and conception prior to
initiation of medication should be considered.
(See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.)
ADDITIONAL INSTRUCTIONS
Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing
oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the
vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent
abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out
pregnancy or malignancy. If pathology has been excluded, time or a change to another
formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen
content, while potentially useful in minimizing menstrual irregularity, should be done only if
necessary since this may increase the risk of thromboembolic disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Use of oral contraceptives in the event of a missed menstrual period:
1. If the patient has not adhered to the prescribed schedule, the possibility of
pregnancy should be considered at the time of the first missed period and oral
contraceptive use should be discontinued if pregnancy is confirmed.
2. If the patient has adhered to the prescribed regimen and misses two consecutive
periods, pregnancy should be ruled out.
HOW SUPPLIED
ORTHO-NOVUM® 7/7/7 Tablets are available in a blister card with a DIALPAK® Tablet
Dispenser (unfilled) (NDC 50458-178-00). The blister card contains 28 tablets, as follows:
7 white, round, flat-faced, beveled edged tablets imprinted with "Ortho 535" on both sides
(0.5 mg norethindrone and 0.035 mg ethinyl estradiol), 7 light peach, round, flat-faced, beveled
edged tablets imprinted with "Ortho 75" on both sides (0.75 mg norethindrone and 0.035 mg
ethinyl estradiol), 7 peach, round, flat-faced, beveled edged tablets imprinted with "Ortho 135"
on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced,
beveled edged tablets imprinted "Ortho" on both sides containing inert ingredients.
ORTHO-NOVUM® 7/7/7 Tablets are packaged in a carton containing 6 blister cards and
6 unfilled DIALPAK® Tablet Dispensers (NDC 50458-178-15).
ORTHO-NOVUM® 7/7/7 is available for clinic usage in a VERIDATE® Tablet Dispenser
(unfilled) and VERIDATE® refills (NDC 50458-178-20).
ORTHO-NOVUM® 1/35 Tablets are available in a blister card with a DIALPAK® Tablet
Dispenser (unfilled) (NDC 50458-176-00). The blister card contains 28 tablets, as follows:
21 peach, round, flat-faced, beveled edged tablets imprinted "Ortho 135" on both sides (1 mg
norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged
tablets imprinted "Ortho" on both sides containing inert ingredients. ORTHO-NOVUM®
1/35 Tablets are packaged in a carton containing 6 blister cards and 6 unfilled DIALPAK®
Tablet Dispensers (NDC 50458-176-15).
MODICON® Tablets are available in a blister card with a DIALPAK® Tablet Dispenser
(unfilled) (NDC 50458-171-00). The blister card contains 28 tablets, as follows: 21 white, round,
flat-faced, beveled edged tablets imprinted "Ortho 535" on both sides (0.5 mg norethindrone and
0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled edged tablets imprinted
"Ortho" on both sides containing inert ingredients. MODICON® Tablets are packaged in a carton
containing 6 blister cards and 6 unfilled DIALPAK® Tablet Dispensers (NDC 50458-171-15).
Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F).
Keep out of reach of children.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
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This label may not be the latest approved by FDA.
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27
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
BRIEF SUMMARY PATIENT PACKAGE INSERT
Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent
pregnancy and when taken correctly without missing any pills, have a failure rate of
approximately 1% per year. The typical failure rate is approximately 5% per year when women
who miss pills are included. For most women oral contraceptives are also free of serious or
unpleasant side effects. However, forgetting to take pills considerably increases the chances of
pregnancy.
For the majority of women, oral contraceptives can be taken safely. But there are some women
who are at high risk of developing certain serious diseases that can be fatal or may cause
temporary or permanent disability. The risks associated with taking oral contraceptives increase
significantly if you:
• smoke
• have high blood pressure, diabetes, high cholesterol
• have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast
or sex organs, jaundice or malignant or benign liver tumors.
Although cardiovascular disease risks may be increased with oral contraceptive use after age 40
in healthy, non-smoking women (even with the newer low-dose formulations), there are also
greater potential health risks associated with pregnancy in older women.
You should not take the pill if you suspect you are pregnant or have unexplained vaginal
bleeding.
Do not use ORTHO-NOVUM® or MODICON® if you smoke cigarettes and are over
35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and
blood vessel problems) from combination oral contraceptives, including death from heart
attack, blood clots or stroke. This risk increases with age and the number of cigarettes you
smoke.
Most side effects of the pill are not serious. The most common such effects are nausea, vomiting,
bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing
contact lenses. These side effects, especially nausea and vomiting, may subside within the first
three months of use.
The serious side effects of the pill occur very infrequently, especially if you are in good health
and are young. However, you should know that the following medical conditions have been
associated with or made worse by the pill:
1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or
rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
(heart attack or angina pectoris) or other organs of the body. As mentioned above,
smoking increases the risk of heart attacks and strokes and subsequent serious medical
consequences.
2. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These
benign liver tumors can rupture and cause fatal internal bleeding. In addition, some
studies report an increased risk of developing liver cancer. However, liver cancers are
rare.
3. High blood pressure, although blood pressure usually returns to normal when the pill is
stopped.
The symptoms associated with these serious side effects are discussed in the detailed leaflet
given to you with your supply of pills. Notify your healthcare professional if you notice any
unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, bosentan,
as well as some seizure medicines and herbal preparations containing St. John’s wort
(Hypericum perforatum) may decrease oral contraceptive effectiveness.
Oral contraceptives may interact with lamotrigine (LAMICTAL®), a seizure medicine used for
epilepsy. This may increase the risk of seizures so your healthcare professional may need to
adjust the dose of lamotrigine.
Various studies give conflicting reports on the relationship between breast cancer and oral
contraceptive use. Oral contraceptive use may slightly increase your chance of having breast
cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you
stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go
back down. You should have regular breast examinations by a healthcare professional and
examine your own breasts monthly. Tell your healthcare professional if you have a family
history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women
who currently have or have had breast cancer should not use oral contraceptives because breast
cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in women who use
oral contraceptives. However, this finding may be related to factors other than the use of oral
contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause
such cancers.
Taking the combination pill provides some important non-contraceptive benefits. These include
less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and
fewer cancers of the ovary and the lining of the uterus.
Be sure to discuss any medical condition you may have with your healthcare professional. Your
healthcare professional will take a medical and family history before prescribing oral
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
contraceptives and will examine you. The physical examination may be delayed to another time
if you request it and the healthcare professional believes that it is a good medical practice to
postpone it. You should be reexamined at least once a year while taking oral contraceptives.
Your pharmacist should have given you the detailed patient information labeling which gives
you further information which you should read and discuss with your healthcare professional.
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not
protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as
chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT
THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK
TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick
to your stomach, do not stop taking the pill. The problem will usually go away. If it
doesn’t go away, check with your healthcare professional.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when
you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick
to your stomach.
5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES,
your pills may not work as well. Use a back-up method (such as a condom or spermicide)
until you check with your healthcare professional.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your
healthcare professional about how to make pill taking easier or about using another
method of birth control.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION
IN THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK.
The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is followed
by 1 week of green "reminder" pills (without hormones).
ORTHO-NOVUM® 7/7/7: There are 7 white "active" pills, 7 light peach "active" pills, 7 peach
"active" pills and 7 green "reminder" pills.
ORTHO-NOVUM® 1/35: There are 21 peach "active" pills and 7 green "reminder" pills.
MODICON®: There are 21 white "active" pills and 7 green "reminder" pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a
back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM® 7/7/7,
ORTHO-NOVUM® 1/35, and MODICON® are available with the DIALPAK® Tablet Dispenser
which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare
professional which is the best day for you. Pick a time of day that will be easy to remember.
SUNDAY START:
ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack on the Sunday after
your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack
the same day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack on the Sunday after
your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack
the same day.
MODICON®: Take the first white "active" pill of the first pack on the Sunday after your period
starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day.
Use another method of birth control such as a condom or spermicide as a back-up method if you
have sex anytime from the Sunday you start your first pack until the next Sunday (7 days).
DAY 1 START:
ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack during the first
24 hours of your period.
ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack during the first
24 hours of your period.
MODICON®: Take the first white "active" pill of the first pack during the first 24 hours of your
period.
You will not need to use a back-up method of birth control, since you are starting the pill at the
beginning of your period.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS
EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel
sick to your stomach (nausea). Do not skip pills even if you do not have sex very often.
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last green "reminder" pill. Do not wait any days
between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO-NOVUM® 7/7/7:
If you MISS 1 white, light peach, or peach "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means you
may take 2 pills in 1 day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light peach "active" pills in a row in WEEK 1 OR WEEK 2 of your
pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 2 peach "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE white, light peach, or peach "active" pills in a row (during the first 3
weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
ORTHO-NOVUM® 1/35:
If you MISS 1 peach "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means you
may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 peach "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 2 peach "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE peach "active" pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
MODICON®:
If you MISS 1 white "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means you
may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 2 white "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE white "active" pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
A REMINDER
If you forget any of the 7 green "reminder" pills in Week 4: THROW AWAY the pills you
missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU
HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your healthcare
professional.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
DETAILED PATIENT LABELING
PLEASE NOTE: This labeling is revised from time to time as important new medical
information becomes available. Therefore, please review this labeling carefully.
The following oral contraceptive products contain a combination of an estrogen and progestogen,
the two kinds of female hormones:
ORTHO-NOVUM® 7/7/7
Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each light
peach tablet contains 0.75 mg norethindrone and 0.035 mg ethinyl estradiol. Each peach tablet
contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet contains inert
ingredients.
ORTHO-NOVUM® 1/35
Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each green tablet
contains inert ingredients.
MODICON®
Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each green
tablet contains inert ingredients.
INTRODUCTION
Any woman who considers using oral contraceptives (the birth control pill or the pill) should
understand the benefits and risks of using this form of birth control. This patient labeling will
give you much of the information you will need to make this decision and will also help you
determine if you are at risk of developing any of the serious side effects of the pill. It will tell
you how to use the pill properly so that it will be as effective as possible. However, this labeling
is not a replacement for a careful discussion between you and your healthcare professional. You
should discuss the information provided in this labeling with him or her, both when you first start
taking the pill and during your revisits. You should also follow your healthcare professional’s
advice with regard to regular check-ups while you are on the pill.
EFFECTIVENESS OF ORAL CONTRACEPTIVES
Oral contraceptives or "birth control pills" or "the pill" are used to prevent pregnancy and are
more effective than other non-surgical methods of birth control. When they are taken correctly
without missing any pills, the chance of becoming pregnant is approximately 1% (1 pregnancy
per 100 women per year of use). Typical failure rates are approximately 5% per year including
women who do not always take the pills exactly as directed. The chance of becoming pregnant
increases with each missed pill during a menstrual cycle.
In comparison, typical failure rates for other methods of birth control during the first year of use
are as follows:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
39
Implant: <1%
Male sterilization: <1%
Injection: <1%
Cervical Cap with spermicides: 20 to 40%
IUD: 1 to 2%
Condom alone (male): 14%
Diaphragm with spermicides: 20%
Condom alone (female): 21%
Spermicides alone: 26%
Periodic abstinence: 25%
Vaginal sponge: 20 to 40%
Withdrawal: 19%
Female sterilization: <1%
No methods: 85%
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Do not use ORTHO-NOVUM® or MODICON® if you smoke cigarettes and are over
35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and
blood vessel problems) from combination oral contraceptives, including death from heart
attack, blood clots or stroke. This risk increases with age and the number of cigarettes you
smoke.
Some women should not use the pill. For example, you should not take the pill if you have any
of the following conditions:
• A history of heart attack or stroke
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
• A history of blood clots in the deep veins of your legs
• An inherited problem that makes your blood clot more than normal
• Chest pain (angina pectoris)
• Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina
• Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare
professional)
• Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during
previous use of the pill
• Liver tumor (benign or cancerous)
• Known or suspected pregnancy
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• If you plan to have surgery with prolonged bed rest
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
• Hypersensitivity to any component of this product.
Tell your healthcare professional if you have ever had any of these conditions. Your healthcare
professional can recommend a safer method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare professional if you have or have had:
• Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or
mammogram
• Diabetes
• Elevated cholesterol or triglycerides
• High blood pressure
• Migraine or other headaches or epilepsy
• Mental depression
• Gallbladder, liver, heart or kidney disease
• History of scanty or irregular menstrual periods
Women with any of these conditions should be checked often by their healthcare professional if
they choose to use oral contraceptives.
Also, be sure to inform your healthcare professional if you smoke or are on any medications.
RISKS OF TAKING ORAL CONTRACEPTIVES
1. Risk of developing blood clots
Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral
contraceptives and can cause death or serious disability. Serious blood clots can happen
especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are
more likely to happen when you:
• First start taking birth control pills
• Restart the same or different birth control pills after not using them for a month or more
In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can
cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the
blood vessels of the eye and may cause blindness, double vision, or impaired vision.
If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged
illness or injury or have recently delivered a baby, you may be at risk of developing blood clots.
You should consult your healthcare professional about stopping oral contraceptives three to four
weeks before surgery and not taking oral contraceptives for two weeks after surgery or during
bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is
advisable to wait for at least four weeks after delivery if you are not breastfeeding or four weeks
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41
after a second trimester abortion. If you are breastfeeding, you should wait until you have
weaned your child before using the pill. (See also the section on Breastfeeding in General
Precautions.)
The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose
pills and may be greater with longer duration of oral contraceptive use. In addition, some of these
increased risks may continue for a number of years after stopping oral contraceptives. The risk of
abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but
the increased risk from the oral contraceptive appears to be present at all ages. For women aged
20 to 44, it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each
year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000
would be hospitalized each year. For oral contraceptive users in general, it has been estimated
that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is
about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age
group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users
and about 1 in 10,000 per year for nonusers.
2. Heart attacks and strokes
Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood
vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the
heart). Any of these conditions can cause death or serious disability.
Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore,
smoking and the use of oral contraceptives greatly increase the chances of developing and dying
of heart disease.
3. Gallbladder disease
Oral contraceptive users probably have a greater risk than nonusers of having gallbladder
disease, although this risk may be related to pills containing high doses of estrogens.
4. Liver tumors
In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign
liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an
increased risk of developing liver cancer. However, liver cancers are rare.
5. Cancer of the reproductive organs and breasts
Various studies give conflicting reports on the relationship between breast cancer and oral
contraceptive use. Oral contraceptive use may slightly increase your chance of having breast
cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you
stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go
back down. You should have regular breast examinations by a healthcare professional and
examine your own breasts monthly. Tell your healthcare professional if you have a family
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
42
history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women
who currently have or have had breast cancer should not use oral contraceptives because breast
cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in women who use
oral contraceptives. However, this finding may be related to factors other than the use of oral
contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause
such cancers.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR
PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing certain
diseases which may lead to disability or death. An estimate of the number of deaths associated
with different methods of birth control and pregnancy has been calculated and is shown in the
following table.
ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH
CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY
CONTROL METHOD ACCORDING TO AGE
Method of control and outcome
15-19
20-24
25-29
30-34
35-39
40-44
No fertility-control methods*
7.0
7.4
9.1
14.8
25.7
28.2
Oral contraceptives non-smoker†
0.3
0.5
0.9
1.9
13.8
31.6
Oral contraceptives smoker†
2.2
3.4
6.6
13.5
51.1
117.2
IUD†
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/ spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
* Deaths are birth-related.
† Deaths are method-related.
In the above table, the risk of death from any birth control method is less than the risk of
childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over
the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39,
the risk of death was highest with pregnancy (7-26 deaths per 100,000 women, depending on
age). Among pill users who do not smoke, the risk of death was always lower than that
associated with pregnancy for any age group, although over the age of 40, the risk increases to
32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However,
for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds
those for other methods of birth control. If a woman is over the age of 40 and smokes, her
estimated risk of death is four times higher (117/100,000 women) than the estimated risk
associated with pregnancy (28/100,000 women) in that age group.
The suggestion that women over 40 who do not smoke should not take oral contraceptives is
based on information from older, higher-dose pills. An Advisory Committee of the FDA
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43
discussed this issue in 1989 and recommended that the benefits of low-dose oral contraceptive
use by healthy, non-smoking women over 40 years of age may outweigh the possible risks.
WARNING SIGNALS
If any of these adverse effects occur while you are taking oral contraceptives, call your
healthcare professional immediately:
• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible
clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain or heaviness in the chest (indicating a possible heart attack)
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or
speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask
your healthcare professional to show you how to examine your breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
• Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly
indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue,
loss of appetite, dark colored urine, or light colored bowel movements (indicating
possible liver problems)
SIDE EFFECTS OF ORAL CONTRACEPTIVES
1. Vaginal bleeding
Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding
may vary from slight staining between menstrual periods to breakthrough bleeding which is a
flow much like a regular period. Irregular bleeding occurs most often during the first few months
of oral contraceptive use, but may also occur after you have been taking the pill for some time.
Such bleeding may be temporary and usually does not indicate any serious problems. It is
important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle
or lasts for more than a few days, talk to your healthcare professional.
2. Contact lenses
If you wear contact lenses and notice a change in vision or an inability to wear your lenses,
contact your healthcare professional.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
44
3. Fluid retention
Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and
may raise your blood pressure. If you experience fluid retention, contact your healthcare
professional.
4. Melasma
A spotty darkening of the skin is possible, particularly of the face, which may persist.
5. Other side effects
Other side effects may include nausea, vomiting and diarrhea, muscle cramps, change in
appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal
infections, pancreatitis, skin sensitivity to the sun or ultraviolet and allergic reactions.
If any of these side effects bother you, call your healthcare professional.
GENERAL PRECAUTIONS
1. Missed periods and use of oral contraceptives before or during early pregnancy
There may be times when you may not menstruate regularly after you have completed taking a
cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue
taking your pills for the next cycle but be sure to inform your healthcare professional before
doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you
may be pregnant. If you missed two consecutive menstrual periods, you may be pregnant. Check
with your healthcare professional immediately to determine whether you are pregnant. Do not
continue to take oral contraceptives until you are sure you are not pregnant, but continue to use
another method of contraception.
There is no conclusive evidence that oral contraceptive use is associated with an increase in birth
defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported
that oral contraceptives might be associated with birth defects, but these findings have not been
seen in more recent studies. Nevertheless, oral contraceptives should not be used during
pregnancy. You should check with your healthcare professional about risks to your unborn child
of any medication taken during pregnancy.
2. While breastfeeding
If you are breastfeeding, consult your healthcare professional before starting oral contraceptives.
Some of the drug will be passed on to the child in the milk. A few adverse effects on the child
have been reported, including yellowing of the skin (jaundice) and breast enlargement. In
addition, combined oral contraceptives may decrease the amount and quality of your milk. If
possible, do not use combined oral contraceptives while breastfeeding. You should use another
method of contraception since breastfeeding provides only partial protection from becoming
pregnant and this partial protection decreases significantly as you breastfeed for longer periods
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
45
of time. You should consider starting combined oral contraceptives only after you have weaned
your child completely.
3. Laboratory tests
If you are scheduled for any laboratory tests, tell your healthcare professional you are taking
birth control pills. Certain blood tests may be affected by birth control pills.
4. Drug interactions
Tell your healthcare provider about all medicines and herbal products that you take.
Some medicines and herbal products may make hormonal birth control less effective, including,
but not limited to:
• certain seizure medicines (carbamazepine, felbamate, oxcarbazepine, phenytoin,
rufinamide, and topiramate)
• aprepitant
• barbiturates
• bosentan
• colesevelam
• griseofulvin
• certain combinations of HIV medicines (nelfinavir, ritonavir, ritonavir-boosted protease
inhibitors)
• certain non nucleoside reverse transcriptase inhibitors (nevirapine)
• rifampin and rifabutin
• St. John’s wort
Use another birth control method (such as a condom and spermicide or diaphragm and
spermicide) when you take medicines that may make ORTHO-NOVUM® 7/7/7,
ORTHO-NOVUM® 1/35, or MODICON® less effective.
Some medicines and grapefruit juice may increase your level of the hormone ethinyl estradiol if
used together, including:
• acetaminophen
• ascorbic acid
• medicines that affect how your liver breaks down other medicines (itraconazole,
ketoconazole, voriconazole, and fluconazole)
• certain HIV medicines (atazanavir, indinavir)
• atorvastatin
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
• rosuvastatin
• etravirine
Hormonal birth control methods may interact with lamotrigine, a seizure medicine used for
epilepsy. This may increase the risk of seizures, so your healthcare provider may need to adjust
the dose of lamotrigine.
Women on thyroid replacement therapy may need increased doses of thyroid hormone.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you
get a new medicine.
5. Sexually transmitted diseases
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not
protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as
chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT
THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK
TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick
to your stomach, do not stop taking the pill. The problem will usually go away. If it
doesn’t go away, check with your healthcare professional.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when
you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick
to your stomach.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES,
your pills may not work as well. Use a back-up method (such as a condom or spermicide)
until you check with your healthcare professional.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your
healthcare professional about how to make pill taking easier or about using another
method of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION
IN THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK.
The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is followed
by 1 week of green "reminder" pills (without hormones).
ORTHO-NOVUM® 7/7/7: There are 7 white "active" pills, 7 light peach "active" pills,
7 peach "active" pills and 7 green "reminder" pills.
ORTHO-NOVUM® 1/35: There are 21 peach "active" pills and 7 green "reminder" pills.
MODICON®: There are 21 white "active" pills and 7 green "reminder" pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR
USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a
back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO-NOVUM® 7/7/7,
ORTHO-NOVUM® 1/35, and MODICON® are available with the DIALPAK® Tablet Dispenser
which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare
professional which is the best day for you. Pick a time of day that will be easy to remember.
SUNDAY START:
ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack on the Sunday after
your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack
the same day.
ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack on the Sunday after
your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack
the same day.
MODICON®: Take the first white "active" pill of the first pack on the Sunday after your period
starts, even if you are still bleeding. If your period begins on Sunday, start the pack the same day.
Use another method of birth control such as a condom or spermicide as a back-up method if you
have sex anytime from the Sunday you start your first pack until the next Sunday (7 days).
DAY 1 START:
ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack during the first
24 hours of your period.
ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack during the first
24 hours of your period.
MODICON®: Take the first white "active" pill of the first pack during the first 24 hours of your
period.
You will not need to use a back-up method of birth control, since you are starting the pill at the
beginning of your period.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS
EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel
sick to your stomach (nausea). Do not skip pills even if you do not have sex very often.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
49
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last green "reminder" pill. Do not wait any days
between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO-NOVUM® 7/7/7:
If you MISS 1 white, light peach, or peach "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means you
may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light peach "active" pills in a row in WEEK 1 OR WEEK 2 of your
pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 2 peach "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
If you MISS 3 OR MORE white, light peach, or peach "active" pills in a row (during the first
3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
ORTHO-NOVUM® 1/35:
If you MISS 1 peach "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means you
may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 peach "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 2 peach "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
51
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE peach "active" pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
MODICON®:
If you MISS 1 white "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means you
may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
52
If you MISS 2 white "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
If you MISS 3 OR MORE white "active" pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack
and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be
pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills.
You MUST use another birth control method (such as a condom or spermicide) as a
back-up method for those 7 days.
A REMINDER
If you forget any of the 7 green "reminder" pills in Week 4: THROW AWAY the pills you
missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
53
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU
HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your healthcare
professional.
PREGNANCY DUE TO PILL FAILURE
Combined Oral Contraceptives
The incidence of pill failure resulting in pregnancy is approximately one percent (i.e., one
pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates
are 5%. If failure does occur, the risk to the fetus is minimal.
PREGNANCY AFTER STOPPING THE PILL
There may be some delay in becoming pregnant after you stop using oral contraceptives,
especially if you had irregular menstrual cycles before you used oral contraceptives. It may be
advisable to postpone conception until you begin menstruating regularly once you have stopped
taking the pill and desire pregnancy.
There does not appear to be any increase in birth defects in newborn babies when pregnancy
occurs soon after stopping the pill.
OVERDOSAGE
Serious ill effects have not been reported following ingestion of large doses of oral
contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in
females. In case of overdosage, contact your healthcare professional or pharmacist.
OTHER INFORMATION
Your healthcare professional will take a medical and family history before prescribing oral
contraceptives and will examine you. The physical examination may be delayed to another time
if you request it and the healthcare professional believes that it is a good medical practice to
postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare
professional if there is a family history of any of the conditions listed previously in this leaflet.
Be sure to keep all appointments with your healthcare professional, because this is a time to
determine if there are early signs of side effects of oral contraceptive use.
Do not use the drug for any condition other than the one for which it was prescribed. This drug
has been prescribed specifically for you; do not give it to others who may want birth control
pills.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
HEALTH BENEFITS FROM ORAL CONTRACEPTIVES
In addition to preventing pregnancy, use of combined oral contraceptives may provide certain
benefits. They are:
• menstrual cycles may become more regular
• blood flow during menstruation may be lighter and less iron may be lost. Therefore,
anemia due to iron deficiency is less likely to occur.
• pain or other symptoms during menstruation may be encountered less frequently
• ectopic (tubal) pregnancy may occur less frequently
• noncancerous cysts or lumps in the breast may occur less frequently
• acute pelvic inflammatory disease may occur less frequently
• oral contraceptive use may provide some protection against developing two forms of
cancer: cancer of the ovaries and cancer of the lining of the uterus.
If you want more information about birth control pills, ask your healthcare professional or
pharmacist. They have a more technical leaflet called the Professional Labeling, which you may
wish to read.
Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F).
Mfd. by:
Janssen Ortho, LLC
Manati, Puerto Rico 00674
Mfd. for:
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised November 2015
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:25.159581
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017735s117,017919s099,018985s063lbl.pdf', 'application_number': 17919, 'submission_type': 'SUPPL ', 'submission_number': 99}
|
11,097
|
NDA 17-962/S-063 & S-064
Package Insert
Page 1
T2003-25
89009903
PARLODEL®
SnapTabs®
(bromocriptine mesylate) tablets, USP
(bromocriptine mesylate) capsules, USP
Rx only
DESCRIPTION
Parlodel® (bromocriptine mesylate) is an ergot derivative with potent dopamine receptor agonist
activity. Each Parlodel® (bromocriptine mesylate) SnapTabs® tablet for oral administration contains
2½ mg and each capsule contains 5 mg bromocriptine (as the mesylate). Bromocriptine mesylate is
chemically designated as Ergotaman-3´,6´,18-trione, 2-bromo-12´-hydroxy-2´-(1-methylethyl)-5´-(2-
methylpropyl)-, (5´α)-mono-methanesulfonate (salt).
The structural formula is:
2½ mg SnapTabs®
Active Ingredient: bromocriptine mesylate, USP
Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and
another ingredient
5 mg Capsules
Active Ingredient: bromocriptine mesylate, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-962/S-063 & S-064
Package Insert
Page 2
Inactive Ingredients: colloidal silicon dioxide, gelatin, lactose, magnesium stearate, red iron oxide,
silicon dioxide, sodium lauryl sulfate, starch, titanium dioxide, yellow iron oxide, and another
ingredient
CLINICAL PHARMACOLOGY
Parlodel® (bromocriptine mesylate) is a dopamine receptor agonist, which activates post-synaptic
dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the
secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to
be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor
function. Clinically, Parlodel significantly reduces plasma levels of prolactin in patients with
physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of
physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at
dose levels that do not affect secretion of other tropic hormones from the anterior pituitary.
Experiments have demonstrated that bromocriptine induces long lasting stereotyped behavior in
rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions,
characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a
direct action of bromocriptine on striatal dopamine receptors.
Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin
in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly,
where it lowers elevated blood levels of growth hormone in the majority of patients.
In about 75% of cases of amenorrhea and galactorrhea, Parlodel therapy suppresses the galactorrhea
completely, or almost completely, and reinitiates normal ovulatory menstrual cycles.
Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on
average is 6-8 weeks. However, some patients respond within a few days, and others may take up to 8
months.
Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue
prior to therapy. At least a 75% reduction in secretion is usually observed after 8-12 weeks. Some
patients may fail to respond even after 12 months of therapy.
In many acromegalic patients, Parlodel produces a prompt and sustained reduction in circulating levels
of serum growth hormone.
Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson’s disease, a
clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia
nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa
exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra,
which are known to be numerically diminished in this patient population.
Pharmacokinetics
The pharmacokinetics and metabolism of bromocriptine in human subjects were studied with the help
of radioactively labeled drug. Twenty-eight percent of an oral dose was absorbed from the
gastrointestinal tract. The blood levels following a 2½ mg dose were in the range of 2-3 ng
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-962/S-063 & S-064
Package Insert
Page 3
equivalents/mL. Plasma levels were in the range of 4-6 ng equivalents/mL indicating that the red blood
cells did not contain appreciable amounts of drug and/or metabolites. In vitro experiments showed that
the drug was 90%-96% bound to serum albumin.
Bromocriptine was completely metabolized prior to excretion. The major route of excretion of
absorbed drug was via the bile. Only 2.5%-5.5% of the dose was excreted in the urine. Almost all
(84.6%) of the administered dose was excreted in the feces in 120 hours.
INDICATIONS AND USAGE
Hyperprolactinemia-Associated Dysfunctions
Parlodel® (bromocriptine mesylate) is indicated for the treatment of dysfunctions associated with
hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or
hypogonadism. Parlodel treatment is indicated in patients with prolactin-secreting adenomas, which
may be the basic underlying endocrinopathy contributing to the above clinical presentations.
Reduction in tumor size has been demonstrated in both male and female patients with
macroadenomas. In cases where adenectomy is elected, a course of Parlodel therapy may be used to
reduce the tumor mass prior to surgery.
Acromegaly
Parlodel therapy is indicated in the treatment of acromegaly. Parlodel therapy, alone or as adjunctive
therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in
approximately ½ of patients treated, although not usually to normal levels.
Since the effects of external pituitary radiation may not become maximal for several years, adjunctive
therapy with Parlodel offers potential benefit before the effects of irradiation are manifested.
Parkinson’s Disease
Parlodel SnapTabs® or capsules are indicated in the treatment of the signs and symptoms of idiopathic
or postencephalitic Parkinson’s disease. As adjunctive treatment to levodopa (alone or with a
peripheral decarboxylase inhibitor), Parlodel therapy may provide additional therapeutic benefits in
those patients who are currently maintained on optimal dosages of levodopa, those who are beginning
to deteriorate (develop tolerance) to levodopa therapy, and those who are experiencing “end of dose
failure’’ on levodopa therapy. Parlodel therapy may permit a reduction of the maintenance dose of
levodopa and, thus may ameliorate the occurrence and/or severity of adverse reactions associated with
long-term levodopa therapy such as abnormal involuntary movements (e.g., dyskinesias) and the
marked swings in motor function (“on-off’’ phenomenon). Continued efficacy of Parlodel therapy
during treatment of more than 2 years has not been established.
Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson’s disease
with Parlodel. Studies have shown, however, significantly more adverse reactions (notably nausea,
hallucinations, confusion and hypotension) in Parlodel treated patients than in levodopa/carbidopa
treated patients. Patients unresponsive to levodopa are poor candidates for Parlodel therapy.
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Package Insert
Page 4
CONTRAINDICATIONS
Uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for
hyperprolactinemia Parlodel® (bromocriptine mesylate) should be withdrawn when pregnancy is
diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that Parlodel is reinstituted
to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a
patient experiences a hypertensive disorder of pregnancy, the benefit of continuing Parlodel must be
weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When
Parlodel is being used to treat acromegaly, prolactinoma, or Parkinson’s disease in patients who
subsequently become pregnant, a decision should be made as to whether the therapy continues to be
medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those
who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or
pregnancy-induced hypertension) unless withdrawal of Parlodel is considered to be medically
contraindicated.
The drug should not be used during the post-partum period in women with a history of coronary artery
disease and other severe cardiovascular conditions unless withdrawal is considered medically
contraindicated. If the drug is used in the post-partum period the patient should be observed with
caution.
WARNINGS
Since hyperprolactinemia with amenorrhea/galactorrhea and infertility has been found in patients with
pituitary tumors, a complete evaluation of the pituitary is indicated before treatment with Parlodel®
(bromocriptine mesylate).
If pregnancy occurs during Parlodel administration, careful observation of these patients is mandatory.
Prolactin-secreting adenomas may expand and compression of the optic or other cranial nerves may
occur, emergency pituitary surgery becoming necessary. In most cases, the compression resolves
following delivery. Reinitiation of Parlodel treatment has been reported to produce improvement in the
visual fields of patients in whom nerve compression has occurred during pregnancy. The safety of
Parlodel treatment during pregnancy to the mother and fetus has not been established.
Symptomatic hypotension can occur in patients treated with Parlodel for any indication. In postpartum
studies with Parlodel, decreases in supine systolic and diastolic pressures of greater than 20 mm and 10
mm Hg, respectively, have been observed in almost 30% of patients receiving Parlodel. On occasion,
the drop in supine systolic pressure was as much as 50-59 mm of Hg. While hypotension during the
start of therapy with Parlodel occurs in some patients, in postmarketing experience in the U.S. in
postpartum patients 89 cases of hypertension have been reported, sometimes at the initiation of
therapy, but often developing in the second week of therapy; seizures have been reported in 72
cases (including 4 cases of status epilepticus), both with and without the prior development of
hypertension; 30 cases of stroke have been reported mostly in postpartum patients whose
prenatal and obstetric courses had been uncomplicated. Many of these patients experiencing
seizures and/or strokes reported developing a constant and often progressively severe headache
hours to days prior to the acute event. Some cases of strokes and seizures were also preceded by
visual disturbances (blurred vision, and transient cortical blindness). Nine cases of acute
myocardial infarction have been reported.
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Package Insert
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Although a causal relationship between Parlodel administration and hypertension, seizures,
strokes, and myocardial infarction in postpartum women has not been established, use of the
drug for prevention of physiological lactation, or in patients with uncontrolled hypertension is
not recommended. In patients being treated for hyperprolactinemia Parlodel should be
withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the
event that Parlodel is reinstituted to control a rapidly expanding macroadenoma (see
PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of
pregnancy, the benefit of continuing Parlodel must be weighed against the possible risk of its use
during a hypertensive disorder of pregnancy. When Parlodel is being used to treat acromegaly
or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made
as to whether the therapy continues to be medically necesssary or can be withdrawn. If it is
continued, the drug should be withdrawn in those who may experience hypertensive disorders of
pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless
withdrawal of Parlodel is considered to be medically contraindicated. Because of the possibility
of an interaction between Parlodel and other ergot alkaloids, the concomitant use of these
medications is not recommended. Particular attention should be paid to patients who have
recently received other drugs that can alter the blood pressure. Periodic monitoring of the blood
pressure, particularly during the first weeks of therapy is prudent. If hypertension, severe, progressive,
or unremitting headache (with or without visual disturbance), or evidence of CNS toxicity develops,
drug therapy should be discontinued and the patient should be evaluated promptly.
Long-term treatment (6-36 months) with Parlodel in doses ranging from 20-100 mg/day has been
associated with pulmonary infiltrates, pleural effusion and thickening of the pleura in a few patients. In
those instances in which Parlodel treatment was terminated, the changes slowly reverted towards
normal.
PRECAUTIONS
General
Safety and efficacy of Parlodel® (bromocriptine mesylate) have not been established in patients with
renal or hepatic disease. Care should be exercised when administering Parlodel therapy concomitantly
with other medications known to lower blood pressure.
The drug should be used with caution in patients with a history of psychosis or cardiovascular disease.
If acromegalic patients or patients with prolactinoma or Parkinson’s disease are being treated with
Parlodel during pregnancy, they should be cautiously observed, particularly during the post-partum
period if they have a history of cardiovascular disease.
Hyperprolactinemic States
Visual field impairment is a known complication of macroprolactinoma. Effective treatment with
Parlodel leads to a reduction in hyperprolactinaemia and often to a resolution of the visual impairment.
In some patients, however, a secondary deterioration of visual fields may subsequently develop despite
normalised prolactin levels and tumor shrinkage, which may result from traction on the optic chiasm
which is pulled down into the now partially empty sella. In these cases the visual field defect may
improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some
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tumour re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore
recommended for an early recognition of secondary field loss due to chiasmal herniation and
adaptation of drug dosage.
The relative efficacy of Parlodel versus surgery in preserving visual fields is not known. Patients with
rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most
appropriate therapy.
Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with
amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is
essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or
those harboring large adenomas, should be advised to use contraceptive measures, other than oral
contraceptives, during treatment with Parlodel. Since pregnancy may occur prior to reinitiation of
menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and,
once menses are reinitiated, every time a patient misses a menstrual period. Treatment with Parlodel
SnapTabs® or capsules should be discontinued as soon as pregnancy has been established. Patients
must be monitored closely throughout pregnancy for signs and symptoms that may signal the
enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of
Parlodel treatment in patients with known macroadenomas has been associated with rapid regrowth of
tumor and increase in serum prolactin in most cases.
Acromegaly
Cold sensitive digital vasospasm has been observed in some acromegalic patients treated with Parlodel.
The response, should it occur, can be reversed by reducing the dose of Parlodel and may be prevented
by keeping the fingers warm. Cases of severe gastrointestinal bleeding from peptic ulcers have been
reported, some fatal. Although there is no evidence that Parlodel increases the incidence of peptic
ulcers in acromegalic patients, symptoms suggestive of peptic ulcer should be investigated thoroughly
and treated appropriately. Patients with a history of peptic ulcer or gastrointestinal bleeding should be
observed carefully during treatment with Parlodel.
Possible tumor expansion while receiving Parlodel therapy has been reported in a few patients. Since
the natural history of growth hormone secreting tumors is unknown, all patients should be carefully
monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative
procedures considered.
Parkinson’s Disease
Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been
established.
As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal
function is recommended. Symptomatic hypotension can occur and, therefore, caution should be
exercised when treating patients receiving antihypertensive drugs.
High doses of Parlodel may be associated with confusion and mental disturbances. Since parkinsonian
patients may manifest mild degrees of dementia, caution should be used when treating such patients.
Parlodel administered alone or concomitantly with levodopa may cause hallucinations (visual or
auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of
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Parlodel is required. Rarely, after high doses, hallucinations have persisted for several weeks following
discontinuation of Parlodel.
As with levodopa, caution should be exercised when administering Parlodel to patients with a history
of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia.
Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2-10 years)
with Parlodel in doses ranging from 30-140 mg daily.
Information for Patients
During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early
in the course of Parlodel therapy. In post-marketing reports, Parlodel has been associated with
somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease.
Sudden onset of sleep during daily activities, in some cases without awarness or warning signs, has
been reported very rarely. All patients receiving Parlodel should be cautioned with regard to engaging
in activities requiring rapid and precise responses, such as driving an automobile or operating
machinery.
Patients receiving Parlodel for hyperprolactinemic states associated with macroadenoma or those who
have had previous transsphenoidal surgery, should be told to report any persistent watery nasal
discharge to their physician. Patients receiving Parlodel for treatment of a macroadenoma should be
told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of
their original symptoms.
Drug Interactions
The risk of using Parlodel in combination with other drugs has not been systematically evaluated, but
alcohol may potentiate the side effects of Parlodel. Parlodel may interact with dopamine antagonists,
butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy
of Parlodel: phenothiazines, haloperidol, metoclopramide, pimozide. Concomitant use of Parlodel with
other ergot alkaloids is not recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to
oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels
equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were
approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled
clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and
myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily,
7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these
neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a
result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed
to be involved in the rats are not present in humans. There is no known correlation between uterine
malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats,
the uteri from mice killed after 74 weeks treatment did not exhibit evidence of drug-related changes.
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Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included
Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts,
cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo
micronucleus test for mutagenic potential in mice.
No mutagenic effects were obtained in any of these tests.
Fertility and reproductive performance in female rats were not influenced adversely by treatment with
bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In
males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased
perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after
mating with males treated with the highest dose (50 mg/kg).
Pregnancy
Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6-15 post
coitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg
given on days 6-15 were without effect on nidation, and did not produce any anomalies. In animals
treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in
the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and
ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg
bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or post-
natal period.
Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation.
Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The
high dose was approximately 63 times the maximum human dose administered in controlled clinical
trials (100 mg/day), based on body surface area. In New Zealand white rabbits some embryo mortality
occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted
in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10,
30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft
palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One
control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits
using an identical protocol, no cleft palates were produced.
No teratological or embryo-toxic effects of bromocriptine were produced in any of 6 offspring from 6
monkeys at a dose level of 2 mg/kg.
Information concerning 1276 pregnancies in women taking Parlodel has been collected. In the majority
of cases, Parlodel was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8
patients received the drug continuously throughout pregnancy. The mean daily dose for all patients
was 5.8 mg (range 1-40 mg).
Of these 1276 pregnancies, there were 1088 full term deliveries (4 stillborn), 145 spontaneous
abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3
hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data
compare favorably with the abortion rate (11%-25%) cited for pregnancies induced by clomiphene
citrate, menopausal gonadotropin, and chorionic gonadotropin.
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Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their
frequency has been estimated to be 15%.
The incidence of birth defects in the population at large ranges from 2%-4.5%. The incidence in 1109
live births from patients receiving bromocriptine is 3.3%.
There is no suggestion that Parlodel contributed to the type or incidence of birth defects in this group
of infants.
Nursing Mothers
Parlodel should not be used during lactation in postpartum women.
Pediatric Use
The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary
adenomas have been established in patients age 16 to adult. No data are available for bromocriptine
use in pediatric patients under the age of 8 years. A single 8-year old patient treated with bromocriptine
for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response.
The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the
age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with
additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with
prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of
the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to
bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the
responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in
combination with surgical treatment and/or pituitary irradiation.
Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other
indication listed in the INDICATIONS AND USAGE section.
Geriatric Use
Clinical studies for Parlodel did not include sufficient numbers of subjects aged 65 and over to
determine whether the elderly respond differently from younger subjects. However, other reported
clinical experiences, including post-marketing reporting of adverse events, have not identified
differences in response or tolerability between elderly and younger patients. Even though no variation
in efficacy or adverse reaction profile in geriatric patients taking Parlodel has been observed, greater
sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose selection for
an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater
frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug
therapy in this population.
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ADVERSE REACTIONS
Hyperprolactinemic Indications
The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in
degree. Therapy was discontinued in approximately 5% of patients because of adverse effects. These in
decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%), fatigue (7%),
lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation
(3%), diarrhea (3%) and drowsiness (3%).
A slight hypotensive effect may accompany Parlodel® (bromocriptine mesylate) treatment. The
occurrence of adverse reactions may be lessened by temporarily reducing dosage to ½ SnapTabs®
tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients
receiving Parlodel for treatment of large prolactinomas. This has occurred rarely, usually only in
patients who have received previous transsphenoidal surgery, pituitary radiation, or both, and who
were receiving Parlodel for tumor recurrence. It may also occur in previously untreated patients whose
tumor extends into the sphenoid sinus.
Acromegaly
The most frequent adverse reactions encountered in acromegalic patients treated with Parlodel were:
nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%), dry
mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%), drowsiness/tiredness
(3%) and vomiting (2%).
Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding, dizziness, exacerbation
of Raynaud’s Syndrome, headache and syncope. Rarely (less than 1%) hair loss, alcohol potentiation,
faintness, lightheadedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual
hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness, vasovagal
attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to cold, tingling
of ears, facial pallor and muscle cramps have been reported.
Parkinson’s Disease
In clinical trials in which Parlodel was administered with concomitant reduction in the dose of
levodopa/carbidopa, the most common newly appearing adverse reactions were: nausea, abnormal
involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness, drowsiness,
faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia,
depression, hypotension, shortness of breath, constipation, and vertigo.
Less common adverse reactions which may be encountered include: anorexia, anxiety, blepharospasm,
dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue,
headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash,
urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism
such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of
Raynaud’s Syndrome.
Pleural and pericardial effusions, pleural, and pulmonary fibrosis or retroperitoneal fibrosis and
constrictive pericarditis have been reported rarely in patients treated with Parlodel.
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Very rarely, a syndrome resembling Neuroleptic Malignant Syndrome has been reported on abrupt
withdrawal of Parlodel.
Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT, GGPT,
CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance.
Adverse Events Observed in Other Conditions
Postpartum Patients
In postpartum studies with Parlodel 23 percent of postpartum patients treated had at least 1 side effect,
but they were generally mild to moderate in degree. Therapy was discontinued in approximately 3% of
patients. The most frequently occurring adverse reactions were: headache (10%), dizziness (8%),
nausea (7%), vomiting (3%), fatigue (1.0%), syncope (0.7%), diarrhea (0.4%) and cramps (0.4%).
Decreases in blood pressure (≥ 20 mm Hg systolic and ≥ 10 mm Hg diastolic) occurred in 28% of
patients at least once during the first 3 postpartum days; these were usually of a transient nature.
Reports of fainting in the puerperium may possibly be related to this effect. In postmarketing
experience in the U.S. serious adverse reactions reported include 72 cases of seizures (including 4
cases of status epilepticus), 30 cases of stroke, and 9 cases of myocardial infarction among postpartum
patients. Seizure cases were not necessarily accompanied by the development of hypertension. An
unremitting and often progressively severe headache, sometimes accompanied by visual disturbance,
often preceded by hours to days many cases of seizure and/or stroke. Most patients had shown no
evidence of any of the hypertensive disorders of pregnancy including eclampsia, preeclampsia or
pregnancy induced hypertension. One stroke case was associated with sagittal sinus thrombosis, and
another was associated with cerebral and cerebellar vasculitis. One case of myocardial infarction was
associated with unexplained disseminated intravascular coagulation and a second occurred in
conjunction with use of another ergot alkaloid. The relationship of these adverse reactions to Parlodel
administration has not been established.
OVERDOSAGE
The most commonly reported signs and symptoms associated with acute Parlodel® (bromocriptine
mesylate) overdose are: nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe
hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive
yawning. The lethal dose has not been established and the drug has a very wide margin of safety.
However, one death occurred in a patient who committed suicide with an unknown quantity of
Parlodel and chloroquine.
Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage,
activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is
essential. Hypotension should be treated by placing the patient in the Trendelenburg position and
administering I.V. fluids. If satisfactory relief of hypotension cannot be achieved by using the above
measures to their fullest extent, vasopressors should be considered.
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DOSAGE AND ADMINISTRATION
General
It is recommended that Parlodel® (bromocriptine mesylate) be taken with food. Patients should be
evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic
response.
Hyperprolactinemic Indications
The initial dosage of Parlodel Snap Tabs® in adults is ½ to one 2½ mg scored tablet daily. An
additional 2½ mg tablet may be added to the treatment regimen as tolerated every 2-7 days until an
optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5-15 mg daily in
adults studied clinically.
Based on limited data in children of age 11 to 15, (see Pediatric Use subsection) the initial dose is ½ to
one 2½ mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic
response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with prolactin-
secreting pituitary adenomas.
In order to reduce the likelihood of prolonged exposure to Parlodel should an unsuspected pregnancy
occur, a mechanical contraceptive should be used in conjunction with Parlodel therapy until normal
ovulatory menstrual cycles have been restored. Contraception may then be discontinued in patients
desiring pregnancy.
Thereafter, if menstruation does not occur within 3 days of the expected date, Parlodel therapy should
be discontinued and a pregnancy test performed.
Acromegaly
Virtually all acromegalic patients receiving therapeutic benefit from Parlodel also have reductions in
circulating levels of growth hormone. Therefore, periodic assessment of circulating levels of growth
hormone will, in most cases, serve as a guide in determining the therapeutic potential of Parlodel. If,
after a brief trial with Parlodel therapy, no significant reduction in growth hormone levels has taken
place, careful assessment of the clinical features of the disease should be made, and if no change has
occurred, dosage adjustment or discontinuation of therapy should be considered.
The initial recommended dosage is ½ to one 2½ mg Parlodel SnapTabs tablet on retiring (with food)
for 3 days. An additional ½ to 1 SnapTabs® tablet should be added to the treatment regimen as
tolerated every 3-7 days until the patient obtains optimal therapeutic benefit. Patients should be
reevaluated monthly and the dosage adjusted based on reductions of growth hormone or clinical
response. The usual optimal therapeutic dosage range of Parlodel varies from 20-30 mg/day in most
patients. The maximal dosage should not exceed 100 mg/day.
Patients treated with pituitary irradiation should be withdrawn from Parlodel therapy on a yearly basis
to assess both the clinical effects of radiation on the disease process as well as the effects of Parlodel
therapy. Usually a 4-8 week withdrawal period is adequate for this purpose. Recurrence of the
signs/symptoms or increases in growth hormone indicate the disease process is still active and further
courses of Parlodel should be considered.
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Parkinson’s Disease
The basic principle of Parlodel therapy is to initiate treatment at a low dosage and, on an individual
basis, increase the daily dosage slowly until a maximum therapeutic response is achieved. The dosage
of levodopa during this introductory period should be maintained, if possible. The initial dose of
Parlodel is ½ of a 2½ mg SnapTabs tablet twice daily with meals. Assessments are advised at 2-week
intervals during dosage titration to ensure that the lowest dosage producing an optimal therapeutic
response is not exceeded. If necessary, the dosage may be increased every 14-28 days by 2½ mg/day
with meals. Should it be advisable to reduce the dosage of levodopa because of adverse reactions, the
daily dosage of Parlodel, if increased, should be accomplished gradually in small (2½ mg) increments.
The safety of Parlodel has not been demonstrated in dosages exceeding 100 mg/day.
HOW SUPPLIED
Parlodel® (bromocriptine mesylate) SnapTabs®
2½ mg
Round, off-white, bevelled-edge SnapTabs®, each containing 2½ mg bromocriptine (as the mesylate).
Engraved “PARLODEL 2½’’ on one side and scored on reverse side. Complies with USP dissolution
test 1.
Packages of 30 .............................................................................NDC 0078-0017-15
Packages of 100 ...........................................................................NDC 0078-0017-05
Parlodel® (bromocriptine mesylate) Capsules
5 mg
Caramel and white capsules, each containing 5 mg bromocriptine (as the mesylate). Imprinted in red
ink “PARLODEL 5 mg’’ on one half and “
’’ on other half
Packages of 30 .............................................................................NDC 0078-0102-15
Packages of 100 ...........................................................................NDC 0078-0102-05
Store and Dispense
Below 25˚C (77˚F); tight, light-resistant container.
T2003-25
REV: March 2003
PRINTED IN USA
89009903
Manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©2003 Novartis
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2025-02-12T13:44:25.225153
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017962s063,064lbl.pdf', 'application_number': 17962, 'submission_type': 'SUPPL ', 'submission_number': 63}
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11,099
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Lopressor®
metoprolol tartrate tablets, USP
metoprolol tartrate injection, USP
Rx only
Prescribing Information
DESCRIPTION
Lopressor, metoprolol tartrate USP, is a selective beta1-adrenoreceptor blocking agent, available
as 50- and 100-mg tablets for oral administration and in 5-mL ampuls for intravenous
administration. Each ampul contains a sterile solution of metoprolol tartrate USP, 5 mg, and
sodium chloride USP, 45 mg, and water for injection USP. Metoprolol tartrate USP is (±)-1
(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its
structural formula is structural formula
Metoprolol tartrate USP is a white, practically odorless, crystalline powder with a molecular
weight of 684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform,
and in alcohol; slightly soluble in acetone; and insoluble in ether.
Inactive Ingredients: Tablets contain cellulose compounds, colloidal silicon dioxide, D&C Red
No. 30 aluminum lake (50-mg tablets), FD&C Blue No. 2 aluminum lake (100-mg tablets),
lactose, magnesium stearate, polyethylene glycol, propylene glycol, povidone, sodium starch
glycolate, talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action:
Lopressor is a beta1-selective (cardioselective) adrenergic receptor blocker. This preferential
effect is not absolute, however, and at higher plasma concentrations, Lopressor also inhibits
beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Clinical pharmacology studies have demonstrated the beta-blocking activity of metoprolol, as
shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of
systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4)
reduction of reflex orthostatic tachycardia.
Hypertension
The mechanism of the antihypertensive effects of beta-blocking agents has not been fully
elucidated. However, several possible mechanisms have been proposed: (1) competitive
antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading
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to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the
periphery; and (3) suppression of renin activity.
Angina Pectoris
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial
contraction, and in blood pressure, Lopressor reduces the oxygen requirements of the heart at any
given level of effort, thus making it useful in the long-term management of angina pectoris.
Myocardial Infarction
The precise mechanism of action of Lopressor in patients with suspected or definite myocardial
infarction is not known.
Pharmacodynamics
Relative beta1 selectivity is demonstrated by the following: (1) In healthy subjects, Lopressor is
unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the
effect of nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating
effects of epinephrine. (2) In asthmatic patients, Lopressor reduces FEV1 and FVC significantly
less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses.
Lopressor has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is
detectable only at doses much greater than required for beta blockade. Animal and human
experiments indicate that Lopressor slows the sinus rate and decreases AV nodal conduction.
Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1
hour after oral administration, and its duration is dose-related. For example, a 50% reduction of
the maximum effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and
6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a
significant reduction in exercise systolic blood pressure was evident at 12 hours. When the drug
was infused over a 10-minute period, in normal volunteers, maximum beta blockade was
achieved at approximately 20 minutes. Equivalent maximal beta-blocking effect is achieved with
oral and intravenous doses in the ratio of approximately 2.5:1.
There is a linear relationship between the log of plasma levels and reduction of exercise heart
rate. However, antihypertensive activity does not appear to be related to plasma levels. Because
of variable plasma levels attained with a given dose and lack of a consistent relationship of
antihypertensive activity to dose, selection of proper dosage requires individual titration.
In several studies of patients with acute myocardial infarction, intravenous followed by oral
administration of Lopressor caused a reduction in heart rate, systolic blood pressure and cardiac
output. Stroke volume, diastolic blood pressure and pulmonary artery end diastolic pressure
remained unchanged.
In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the
oral dose within the range of 50-400 mg. Exercise heart rate and systolic blood pressure are
reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise
capacity and the reduction in left ventricular ischemia are also significantly related to the
logarithm of the oral dose.
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Pharmacokinetics
Absorption: The estimated oral bioavailability of immediate release metoprolol is about 50%
because of pre-systemic metabolism which is saturable leading to non-proportionate increase in
the exposure with increased dose.
Distribution: Metoprolol is extensively distributed with a reported volume of distribution of 3.2
to 5.6 L/kg. About 10% of metoprolol in plasma is bound to serum albumin. Metoprolol is known
to cross the placenta and is found in breast milk. Metoprolol is also known to cross the blood
brain barrier following oral administration and CSF concentrations close to that observed in
plasma have been reported. Metoprolol is not a significant P-glycoprotein substrate
Metabolism: Lopressor is primarily metabolized by CYP2D6. Metoprolol is a racemic mixture of
R- and S- enantiomers, and when administered orally, it exhibits stereoselective metabolism that
is dependent on oxidation phenotype. CYP2D6 is absent (poor metabolizers) in about 8% of
Caucasians and about 2% of most other populations. Poor CYP2D6 metabolizers exhibit several
fold higher plasma concentrations of Lopressor than extensive metabolizers with normal
CYP2D6 activity thereby decreasing Lopressor’s cardioselectivity.
Elimination: Elimination of Lopressor is mainly by biotransformation in the liver. The mean
elimination half-life of metoprolol is 3 to 4 hours; in poor CYP2D6 metabolizers the half-life
may be 7 to 9 hours. Approximately 95% of the dose can be recovered in urine. In most subjects
(extensive metabolizers), less than 5% of an oral dose and less than 10% of an intravenous dose
are excreted as unchanged drug in the urine. In poor metabolizers, up to 30% or 40% of oral or
intravenous doses, respectively, may be excreted unchanged; the rest is excreted by the kidneys
as metabolites that appear to have no beta blocking activity. The renal clearance of the stereo-
isomers does not exhibit stereo-selectivity in renal excretion.
Special populations
Geriatric patients: The geriatric population may show slightly higher plasma concentrations of
metoprolol as a combined result of a decreased metabolism of the drug in elderly population and
a decreased hepatic blood flow. However, this increase is not clinically significant or
therapeutically relevant.
Renal impairment: The systemic availability and half-life of Lopressor in patients with renal
failure do not differ to a clinically significant degree from those in normal subjects.
Hepatic Impairment: Since the drug is primarily eliminated by hepatic metabolism, hepatic
impairment may impact the pharmacokinetics of metoprolol. The elimination half-life of
metoprolol is considerably prolonged, depending on severity (up to 7.2 h).
Clinical Studies:
Hypertension
In controlled clinical studies, Lopressor has been shown to be an effective antihypertensive agent
when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100
450 mg daily. In controlled, comparative, clinical studies, Lopressor has been shown to be as
effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, to be
equally effective in supine and standing positions.
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Angina Pectoris
In controlled clinical trials, Lopressor, administered two or four times daily, has been shown to be
an effective antianginal agent, reducing the number of angina attacks and increasing exercise
tolerance. The dosage used in these studies ranged from 100-400 mg daily. A controlled,
comparative, clinical trial showed that Lopressor was indistinguishable from propranolol in the
treatment of angina pectoris.
Myocardial Infarction
In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, Lopressor
was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial
infarction.
Patients were randomized and treated as soon as possible after their arrival in the hospital, once
their clinical condition had stabilized and their hemodynamic status had been carefully evaluated.
Subjects were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or
more than minimal basal rales as signs of congestive heart failure. Initial treatment consisted of
intravenous followed by oral administration of Lopressor or placebo, given in a coronary care or
comparable unit. Oral maintenance therapy with Lopressor or placebo was then continued for
3 months. After this double-blind period, all patients were given Lopressor and followed up to
1 year.
The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the
Lopressor- and placebo-treatment groups. Among patients treated with Lopressor, there were
comparable reductions in 3-month mortality for those treated early (≤8 hours) and those in whom
treatment was started later. Significant reductions in the incidence of ventricular fibrillation and
in chest pain following initial intravenous therapy were also observed with Lopressor and were
independent of the interval between onset of symptoms and initiation of therapy.
In this study, patients treated with metoprolol received the drug both very early (intra-venously)
and during a subsequent 3-month period, while placebo patients received no beta-blocker
treatment for this period. The study thus was able to show a benefit from the overall metoprolol
regimen but cannot separate the benefit of very early intravenous treatment from the benefit of
later beta-blocker therapy. Nonetheless, because the overall regimen showed a clear beneficial
effect on survival without evidence of an early adverse effect on survival, one acceptable dosage
regimen is the precise regimen used in the trial. Because the specific benefit of very early
treatment remains to be defined however, it is also reasonable to administer the drug orally to
patients at a later time as is recommended for certain other beta blockers.
INDICATIONS AND USAGE
Hypertension
Lopressor tablets are indicated for the treatment of hypertension. They may be used alone or in
combination with other antihypertensive agents.
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Angina Pectoris
Lopressor is indicated in the long-term treatment of angina pectoris.
Myocardial Infarction
Lopressor ampuls and tablets are indicated in the treatment of hemodynamically stable patients
with definite or suspected acute myocardial infarction to reduce cardiovascular mortality.
Treatment with intravenous Lopressor can be initiated as soon as the patient’s clinical condition
allows (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and
WARNINGS). Alternatively, treatment can begin within 3 to 10 days of the acute event (see
DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Hypertension and Angina
Lopressor is contraindicated in sinus bradycardia, heart block greater than first degree,
cardiogenic shock, and overt cardiac failure (see WARNINGS).
Hypersensitivity to Lopressor and related derivatives, or to any of the excipients; hypersensitivity
to other beta blockers (cross sensitivity between beta blockers can occur).
Sick-sinus syndrome.
Severe peripheral arterial circulatory disorders.
Myocardial Infarction
Lopressor is contraindicated in patients with a heart rate <45 beats/min; second- and third-degree
heart block; significant first-degree heart block (P-R interval ≥0.24 sec); systolic blood pressure
<100 mmHg; or moderate-to-severe cardiac failure (see WARNINGS).
WARNINGS
Hypertension and Angina
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in
congestive heart failure, and beta blockade carries the potential hazard of further depressing
myocardial contractility and precipitating more severe failure.
In Patients Without a History of Cardiac Failure: Continued depression of the myocardium
with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the
first sign or symptom of impending cardiac failure, fully digitalize patients and/or give a diuretic.
The response should be observed closely. If cardiac failure continues, despite adequate
digitalization and diuretic therapy, withdraw Lopressor.
Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking
agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred.
When discontinuing chronically administered Lopressor, particularly in patients with ischemic
heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient
should be carefully monitored. If angina markedly worsens or acute coronary insufficiency
develops, Lopressor administration should be reinstated promptly, at least temporarily, and other
measures appropriate for the management of unstable angina should be taken. Patients should be
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warned against interruption or discontinuation of therapy without the physician’s advice. Because
coronary artery disease is common and may be unrecognized, it may be prudent not to
discontinue Lopressor therapy abruptly even in patients treated only for hypertension.
Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD,
IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Lopressor. Because of its
relative beta1 selectivity, however, Lopressor may be used with caution in patients with
bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive
treatment. Since beta1 selectivity is not absolute, a beta2-stimulating agent should be
administered concomitantly, and the lowest possible dose of Lopressor should be used. In
these circumstances it would be prudent initially to administer Lopressor in smaller doses
three times daily, instead of larger doses two times daily, to avoid the higher plasma levels
associated with the longer dosing interval (see DOSAGE AND ADMINISTRATION).
Major Surgery:
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major
surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may
augment the risks of general anesthesia and surgical procedures.
Diabetes and Hypoglycemia: Beta blockers may mask tachycardia occurring with hypoglycemia,
but other manifestations such as dizziness and sweating may not be significantly affected.
Pheochromocytoma: If Lopressor is used in the setting of pheochromocytoma, it should be
given in combination with an alpha blocker, and only after the alpha blocker has been initiated.
Administration of beta blockers alone in the setting of pheochromocytoma has been associated
with a paradoxical increase in blood pressure due to the attenuation of beta-mediated
vasodilatation in skeletal muscle.
Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of
hyperthyroidism. Avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid
storm.
Myocardial Infarction
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function,
and beta blockade carries the potential hazard of depressing myocardial contractility and
precipitating or exacerbating minimal cardiac failure.
During treatment with Lopressor, monitor the hemodynamic status of the patient. If heart failure
occurs or persists despite appropriate treatment, discontinue Lopressor.
Bradycardia: Lopressor produces a decrease in sinus heart rate in most patients; this decrease is
greatest among patients with high initial heart rates and least among patients with low initial heart
rates. Acute myocardial infarction (particularly inferior infarction) may in itself produce
significant lowering of the sinus rate. If the sinus rate decreases to <40 beats/min, particularly if
associated with evidence of lowered cardiac output, atropine (0.25-0.5 mg) should be
administered intravenously. If treatment with atropine is not successful, discontinue Lopressor
and consider cautious administration of isoproterenol or installation of a cardiac pacemaker.
AV Block: Lopressor slows AV conduction and may produce significant first- (P-R interval
≥0.26 sec), second-, or third-degree heart block. Acute myocardial infarction also produces heart
block.
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If heart block occurs, discontinue Lopressor and administer atropine (0.25-0.5 mg) intravenously.
If treatment with atropine is not successful, consider administration of isoproterenol or
installation of a cardiac pacemaker.
Hypotension: If hypotension (systolic blood pressure ≤90 mmHg) occurs, discontinue Lopressor,
and assess the hemodynamic status of the patient and the extent of myocardial damage. Invasive
monitoring of central venous, pulmonary capillary wedge, and arterial pressures may be required.
Institute appropriate therapy with fluids, positive inotropic agents, balloon counterpulsation, or
other treatment modalities. If hypotension is associated with sinus bradycardia or AV block,
direct treatment at reversing these (see above).
PRECAUTIONS
General
Start at a low dose and uptitrate slowly in patients with impaired hepatic function.
Information for Patients
Advise patients to take Lopressor regularly and continuously, as directed, with or immediately
following meals. If a dose should be missed, the patient should take only the next scheduled dose
(without doubling it). Patients should not discontinue Lopressor without consulting the physician.
Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks
requiring alertness until the patient’s response to therapy with Lopressor has been determined; (2)
to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist
before any type of surgery that he or she is taking Lopressor.
Drug Interactions
Catecholamine-depleting drugs: Catecholamine-depleting drugs (e.g., reserpine) may have an
additive effect when given with beta-blocking agents or monoamine oxidase (MAO) inhibitors.
Observe patients treated with Lopressor plus a catecholamine depletor for evidence of
hypotension or marked bradycardia, which may produce vertigo, syncope, or postural
hypotension. In addition, possibly significant hypertension may theoretically occur up to 14 days
following discontinuation of the concomitant administration with an irreversible MAO inhibitor.
Digitalis glycosides and beta blockers: Both digitalis glycosides and beta blockers slow
atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of
bradycardia. Monitor heart rate and PR interval.
Calcium channel blockers: Concomitant administration of a beta-adrenergic antagonist with a
calcium channel blocker may produce an additive reduction in myocardial contractility because
of negative chronotropic and inotropic effects.
Risk of Anaphylactic Reaction: While taking beta blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat allergic reaction.
General Anesthetics: Some inhalation anesthetics may enhance the cardiodepressant effect of
beta blockers (see WARNINGS, Major Surgery).
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CYP2D6 Inhibitors: Potent inhibitors of the CYP2D6 enzyme may increase the plasma
concentration of Lopressor which would mimic the pharmacokinetics of CYP2D6 poor
metabolizer (see Pharmacokinetics section). Increase in plasma concentrations of metoprolol
would decrease the cardioselectivity of metoprolol. Known clinically significant potent inhibitors
of CYP2D6 are antidepressants such as fluvoxamine, fluoxetine, paroxetine, sertraline,bupropion,
clomipramine, and desipramine; antipsychotics such as chlorpromazine, fluphenazine,
haloperidol, and thioridazine; antiarrhythmics such as quinidine or propafenone; antiretrovirals
such as ritonavir; antihistamines such as diphenhydramine; antimalarials such as
hydroxychloroquine or quinidine; antifungals such as terbinafine.
Hydralazine: Concomitant administration of hydralazine may inhibit presystemic metabolism of
metoprolol leading to increased concentrations of metoprolol.
Alpha-adrenergic agents: Antihypertensive effect of alpha-adrenergic blockers such as
guanethidine, betanidine, reserpine, alpha-methyldopa or clonidine may be potentiated by beta-
blockers including Lopressor. Beta- adrenergic blockers may also potentiate the postural
hypotensive effect of the first dose of prazosin, probably by preventing reflex tachycardia. On the
contrary, beta adrenergic blockers may also potentiate the hypertensive response to withdrawal of
clonidine in patients receiving concomitant clonidine and beta-adrenergic blocker. If a patient is
treated with clonidine and Lopressor concurrently, and clonidine treatment is to be discontinued,
stop Lopressor several days before clonidine is withdrawn. Rebound hypertension that can follow
withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.
Ergot alkaloid: Concomitant administration with beta-blockers may enhance the vasoconstrictive
action of ergot alkaloids.
Dipyridamole: In general, administration of a beta-blocker should be withheld before
dipyridamole testing, with careful monitoring of heart rate following the dipyridamole injection.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year
study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the
development of spontaneously occurring benign or malignant neoplasms of any type. The only
histologic changes that appeared to be drug related were an increased incidence of generally mild
focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary
hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to
750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female
mice receiving the highest dose than in untreated control animals. There was no increase in
malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or
malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or
biologically significant differences were observed between treated and control mice of either sex
for any type of tumor.
All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in
somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test
in somatic interphase nuclei) were negative.
Reproduction toxicity studies in mice, rats and rabbits did not indicate teratogenic potential for
metoprolol tartrate. Embryotoxicity and/or fetotoxicity in rats and rabbits were noted starting at
doses of 50 mg/kg in rats and 25 mg/kg in rabbits, as demonstrated by increases in
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preimplantation loss, decreases in the number of viable fetuses per dose, and/or decreases in
neonatal survival. High doses were associated with some maternal toxicity, and growth delay of
the offspring in utero, which was reflected in minimally lower weights at birth. The oral NOAELs
for embryo-fetal development in mice, rats, and rabbits were considered to be 25, 200, and 12.5
mg/kg. This corresponds to dose levels that are approximately 0.3, 4, and 0.5 times, respectively,
when based on surface area, the maximum human oral dose (8 mg/kg/day) of metoprolol tartrate.
Metoprolol tartrate has been associated with reversible adverse effects on spermatogenesis
starting at oral dose levels of 3.5 mg/kg in rats (a dose that is only 0.1-times the human dose,
when based on surface area), although other studies have shown no effect of metoprolol tartrate
on reproductive performance in male rats.
Pregnancy Category C
Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.
Lopressor has been shown to increase postimplantation loss and decrease neonatal survival in rats
at doses up to 11 times the maximum daily human dose of 450 mg, when based on surface area.
Distribution studies in mice confirm exposure of the fetus when Lopressor is administered to the
pregnant animal. These limited animal studies do not indicate direct or indirect harmful effects
with respect to teratogenicity (see Carcinogenesis, Mutagenesis, Impairment of Fertility).
There are no adequate and well-controlled studies in pregnant women. The amount of data on the
use of metoprolol in pregnant women is limited. The risk to the fetus/mother is unknown.
Because animal reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.
Nursing Mothers
Lopressor is excreted in breast milk in a very small quantity. An infant consuming 1 liter of
breast milk daily would receive a dose of less than 1 mg of the drug.
Fertility
The effects of Lopressor on the fertility of human have not been studied.
Lopressor showed effects on spermatogenesis in male rats at a therapeutic dose level, but had no
effect on rates of conception at higher doses in animal fertility studies (see Carcinogenesis,
Mutagenesis, Impairment of Fertility).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical trials of Lopressor in hypertension did not include sufficient numbers of elderly patients
to determine whether patients over 65 years of age differ from younger subjects in their response
to Lopressor. Other reported clinical experience in elderly hypertensive patients has not identified
any difference in response from younger patients.
In worldwide clinical trials of Lopressor in myocardial infarction, where approximately 478
patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety
and effectiveness were found. Other reported clinical experience in myocardial infarction has not
identified differences in response between the elderly and younger patients. However, greater
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sensitivity of some elderly individuals taking Lopressor cannot be categorically ruled out.
Therefore, in general, it is recommended that dosing proceed with caution in this population.
ADVERSE REACTIONS
Hypertension and Angina
Most adverse effects have been mild and transient.
Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients.
Depression has been reported in about 5 of 100 patients. Mental confusion and short-term
memory loss have been reported. Headache, nightmares, and insomnia have also been reported.
Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100
patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations;
congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100
patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also
been reported very rarely. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS.)
Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100
patients (see WARNINGS). Rhinitis has also been reported.
Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric
pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients.
Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of
hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline
phosphatase, and lactic dehydrogenase elevations have also been reported.
Hypersensitive Reactions: Pruritus or rash have occurred in about 5 of 100 patients. Very rarely,
photosensitivity and worsening of psoriasis has been reported.
Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients.
Musculoskeletal pain, blurred vision, and tinnitus have also been reported.
There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes.
Discontinuation of the drug should be considered if any such reaction is not otherwise explicable.
There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis
(relationship to Lopressor has not been definitely established).
The oculomucocutaneous syndrome associated with the beta blocker practolol has not been
reported with Lopressor.
Myocardial Infarction
Central Nervous System: Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep
disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced
libido have also been reported, but a drug relationship is not clear.
Cardiovascular: In the randomized comparison of Lopressor and placebo described in the
CLINICAL PHARMACOLOGY section, the following adverse reactions were reported:
Lopressor®
Placebo
Hypotension (systolic BP <90 mmHg)
27.4%
23.2%
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Lopressor®
Placebo
Bradycardia (heart rate <40 beats/min)
15.9%
6.7%
Second- or third-degree heart block
4.7%
4.7%
First-degree heart block (P-R ≥0.26 sec)
5.3%
1.9%
Heart failure
27.5%
29.6%
Respiratory: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients.
Gastrointestinal: Nausea and abdominal pain have been reported in fewer than 1 of 100 patients.
Dermatologic: Rash and worsened psoriasis have been reported, but a drug relationship is not
clear.
Miscellaneous: Unstable diabetes and claudication have been reported, but a drug relationship is
not clear.
Potential Adverse Reactions
A variety of adverse reactions not listed above have been reported with other beta-adrenergic
blocking agents and should be considered potential adverse reactions to Lopressor.
Central Nervous System: Reversible mental depression progressing to catatonia; an acute
reversible syndrome characterized by disorientation for time and place, short-term memory loss,
emotional lability, slightly clouded sensorium, and decreased performance on
neuropsychometrics.
Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm and
respiratory distress.
Postmarketing Experience
The following adverse reactions have been reported during postapproval use of Lopressor:
confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein
(HDL). Because these reports are from a population of uncertain size and are subject to
confounding factors, it is not possible to reliably estimate their frequency.
OVERDOSAGE
Acute Toxicity
Several cases of overdosage have been reported, some leading to death.
Oral LD 50’s (mg/kg): mice, 1158-2460; rats, 3090-4670.
Signs and Symptoms
Potential signs and symptoms associated with overdosage with Lopressor are bradycardia,
hypotension, bronchospasm, myocardial infarction, cardiac failure and death.
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Management
There is no specific antidote.
In general, patients with acute or recent myocardial infarction may be more hemodynamically
unstable than other patients and should be treated accordingly (see WARNINGS, Myocardial
Infarction).
On the basis of the pharmacologic actions of Lopressor, the following general measures should be
employed:
Elimination of the Drug: Gastric lavage should be performed.
Other clinical manifestations of overdose should be managed symptomatically based on modern
methods of intensive care.
Hypotension: Administer a vasopressor, e.g., levarterenol or dopamine.
Bronchospasm: Administer a beta2-stimulating agent and/or a theophylline derivative.
Cardiac Failure: Administer digitalis glycoside and diuretic. In shock resulting from inadequate
cardiac contractility, consider administration of dobutamine, isoproterenol or glucagon.
DOSAGE AND ADMINISTRATION
Hypertension
Individualize the dosage of Lopressor tablets. Lopressor tablets should be taken with or
immediately following meals.
The usual initial dosage of Lopressor tablets is 100 mg daily in single or divided doses, whether
used alone or added to a diuretic. Increase the dosage at weekly (or longer) intervals until
optimum blood pressure reduction is achieved. In general, the maximum effect of any given
dosage level will be apparent after 1 week of therapy. The effective dosage range of Lopressor
tablets is 100-450 mg per day. Dosages above 450 mg per day have not been studied. While once-
daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower
doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and
larger or more frequent daily doses may be required. This can be evaluated by measuring blood
pressure near the end of the dosing interval to determine whether satisfactory control is being
maintained throughout the day. Beta1 selectivity diminishes as the dose of Lopressor is increased.
Angina Pectoris
The dosage of Lopressor tablets should be individualized. Lopressor tablets should be taken with
or immediately following meals.
The usual initial dosage of Lopressor tablets is 100 mg daily, given in two divided doses.
gradually increase the dosage at weekly intervals until optimum clinical response has been
obtained or there is pronounced slowing of the heart rate. The effective dosage range of
Lopressor tablets is 100-400 mg per day. Dosages above 400 mg per day have not been studied. If
treatment is to be discontinued, gradually decrease the dosage over a period of 1-2 weeks (see
WARNINGS).
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Myocardial Infarction
Early Treatment: During the early phase of definite or suspected acute myocardial infarction,
initiate treatment with Lopressor as soon as possible after the patient’s arrival in the hospital.
Such treatment should be initiated in a coronary care or similar unit immediately after the
patient’s hemodynamic condition has stabilized.
Begin treatment in this early phase with the intravenous administration of three bolus injections
of 5 mg of Lopressor each; give the injections at approximately 2-minute intervals. During the
intravenous administration of Lopressor, monitor blood pressure, heart rate, and
electrocardiogram.
In patients who tolerate the full intravenous dose (15 mg), initiate Lopressor tablets, 50 mg every
6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the
maintenance dosage is 100 mg twice daily (see Late Treatment below).
Start patients who appear not to tolerate the full intravenous dose on Lopressor tablets either
25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last
intravenous dose or as soon as their clinical condition allows. In patients with severe intolerance,
discontinue Lopressor (see WARNINGS).
Late Treatment: Start patients with contraindications to treatment during the early phase of
suspected or definite myocardial infarction, patients who appear not to tolerate the full early
treatment, and patients in whom the physician wishes to delay therapy for any other reason on
Lopressor tablets, 100 mg twice daily, as soon as their clinical condition allows. Continue therapy
for at least 3 months. Although the efficacy of Lopressor beyond 3 months has not been
conclusively established, data from studies with other beta blockers suggest that treatment should
be continued for 1-3 years.
Special populations
Pediatric patients: No pediatric studies have been performed. The safety and efficacy of
Lopressor in pediatric patients have not been established.
Renal impairment: No dose adjustment of Lopressor is required in patients with renal
impairment.
Hepatic impairment: Lopressor blood levels are likely to increase substantially in patients with
hepatic impairment. Therefore, Lopressor should be initiated at low doses with cautious gradual
dose titration according to clinical response.
Geriatric patients (>65 years): In general, use a low initial starting dose in elderly patients given
their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
Method of administration:
Parenteral administration of Lopressor (ampoule) should be done in a setting with intensive
monitoring.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
For oral treatment, the tablets should be swallowed un-chewed with a glass of water. Lopressor
should always be taken in standardized relation with meals. If the physician asks the patient to
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take Lopressor either before breakfast or with breakfast, then the patient should continue taking
Lopressor with the same schedule during the course of therapy.
HOW SUPPLIED
Lopressor® Tablets
metoprolol tartrate tablets, USP
Tablets 50 mg – capsule-shaped, biconvex, pink, scored (imprinted GEIGY on one side and 51
twice on the scored side)
Bottles of 100 ................................................................................................ NDC 0078-0458-05
Tablets 100 mg – capsule-shaped, biconvex, light blue, scored (imprinted GEIGY on one side
and 71 twice on the scored side)
Bottles of 100 ................................................................................................ NDC 0078-0459-05
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from moisture and heat.
Dispense in tight, light-resistant container (USP).
Lopressor® Injection
metoprolol tartrate injection, USP
Ampuls 5 mL – each containing 5 mg of metoprolol tartrate
Carton of 10 ampuls ...................................................................................... NDC 0078-0400-01
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from light and heat.
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals
Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Tablets manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Ampuls manufactured by:
Novartis Pharma Stein AG
Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
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East Hanover, New Jersey 07936
T2012-XX
December 2012
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---------------------------------------------------------------------------------------------------------
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----------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
MARY R SOUTHWORTH
12/21/2012
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2025-02-12T13:44:25.478422
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017963s067lbl.pdf', 'application_number': 17963, 'submission_type': 'SUPPL ', 'submission_number': 67}
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company logo
Parlodel®
SnapTabs®
(bromocriptine mesylate) tablets, USP
(bromocriptine mesylate) capsules, USP
Rx only
Prescribing Information
DESCRIPTION
Parlodel® (bromocriptine mesylate) is an ergot derivative with potent dopamine receptor agonist
activity. Each Parlodel® (bromocriptine mesylate) SnapTabs® tablet for oral administration
contains 2½ mg and each capsule contains 5 mg bromocriptine (as the mesylate). Bromocriptine
mesylate is chemically designated as Ergotaman-3′,6′,18-trione, 2-bromo-12′-hydroxy-2′-
(1-methylethyl)-5′-(2-methylpropyl)-, (5′α)-monomethanesulfonate (salt).
The structural formula is: structural formula
2½ mg SnapTabs®
Active Ingredient: bromocriptine mesylate, USP
Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and
another ingredient
5 mg Capsules
Active Ingredient: bromocriptine mesylate, USP
Inactive Ingredients: colloidal silicon dioxide, gelatin, lactose, magnesium stearate, red iron
oxide, silicon dioxide, sodium lauryl sulfate, starch, titanium dioxide, yellow iron oxide, and
another ingredient
CLINICAL PHARMACOLOGY
Parlodel® (bromocriptine mesylate) is a dopamine receptor agonist, which activates post-synaptic
dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the
Reference ID: 3067506
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secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor
(thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the
control of motor function. Clinically, Parlodel significantly reduces plasma levels of prolactin in
patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia.
The inhibition of physiological lactation as well as galactorrhea in pathological
hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic
hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces
long-lasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions
in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited
by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine
receptors.
Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of
prolactin in humans, with little or no effect on other pituitary hormones, except in patients with
acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients.
Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson’s disease, a
clinical condition characterized by a progressive deficiency in dopamine synthesis in the
substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In
contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons
of the substantia nigra, which are known to be numerically diminished in this patient population.
Clinical Studies
In about 75% of cases of amenorrhea and galactorrhea, Parlodel therapy suppresses the
galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles.
Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on
average is 6-8 weeks. However, some patients respond within a few days, and others may take up
to 8 months.
Galactorrhea may take longer to control depending on the degree of stimulation of the mammary
tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8-12 weeks.
Some patients may fail to respond even after 12 months of therapy.
In many acromegalic patients, Parlodel produces a prompt and sustained reduction in circulating
levels of serum growth hormone.
Pharmacokinetics
Absorption
Following single dose administration of Parlodel tablets, 2 x 2.5 mg to 5 healthy volunteers under
fasted conditions, the mean peak plasma levels of bromocriptine, time to reach peak plasma
concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hrs ± 2 and 4.85 hr,
respectively.1 Linear relationship was found between single doses of Parlodel and Cmax and AUC
in the dose range of 1 to 7.5 mg.2 The pharmacokinetics of bromocriptine metabolites have not
been reported.
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____________________________________________________
Food did not significantly affect the systemic exposure of bromocriptine following
administration of Parlodel tablets, 2.5 mg.3 It is recommended that Parlodel be taken with food
because of the high percentage of subjects who vomit upon receiving bromocriptine under fasting
conditions.
Following Parlodel 5 mg administered twice daily for 14 days, the bromocriptine Cmax and AUC
at steady state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively.4
Distribution
In vitro experiments showed that bromocriptine was 90%-96% bound to serum albumin.
Metabolism
Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite
profiles and by almost complete absence of parent drug in urine and feces.
In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for
CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main
metabolic pathway. 5 Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the
clearance of bromocriptine and lead to increased levels. (see PRECAUTIONS, drug interactions
section). The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 on the
metabolism of bromocriptine has not been evaluated. Bromocriptine is also an inhibitor of
CYP3A4 with a calculated IC50 value of 1.69 μM.6 Given the low therapeutic concentrations of
bromocriptine in patients (Cmax=0.82 nM), a significant alteration of the metabolism of a second
drug whose clearance is mediated by CYP3A4 should not be expected. The potential effect of
bromocriptine and its metabolites to act as inducers of CYP enzymes has not been reported.
Excretion
About 82% and 5.6 % of the radioactive dose orally administered was recovered in feces and
urine, respectively. Bromolysergic acid and bromoisolysergic acid accounted for half of the
radioactivity in urine.5
1 Nelson, M. et. al. (1990). Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine. Clin
Pharmacol Ther; 47(6):694-7.
2Schran, H.F., Bhuta, S.I., Schwartz, et al. (1980). The pharmacokinetics of bromocriptine in man. In: Golstein, M. Calne,
D.B.,et. Al (eds). Ergot compound and brain function: Neuroendocrine and neuropsychiatric aspects, pp. 125-139, New York,
Rave Press.
3 Kopitar, Z., Vrhovac, B., Povsic, L., Plavsic, F., Francetic, I., Urbancic, J. (1991). The effect of food and metoclopramide on the
pharmacokinetics and side effects of bromocriptine. Eur J Drug Metab Pharmacokinet; 16(3):177-81
4 Flogstad, A.K., Halse, J., Grass, P., Abisch, E., Djoseland, O., Kutz, K., Bodd, E., and Jervell, J., (1994). A comparison of
octreotide, bromocriptine, or a combination of both drugs in acromegaly. Journal of Clinical Endocrinology & Metabolism; Vol
79, 461-465
5 Peyronneau MA, Delaforge M, Riviere R et al. 1994. High affinity of ergopeptides for CYP P450 3A. Importance of their
peptide moiety for P450 recognition and hydroxylation of bromocriptine. Eur J Biochem 223:947-56.
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Special Populations
Effect of Renal Impairment
The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated.
Since parent drug and metabolites are almost completely excreted via metabolism, and only 6%
eliminated via the kidney, renal impairment may not have a significant impact on the PK of
bromocriptine and its metabolites (see PRECAUTIONS, general).
Effect of Liver Impairment
The effect of liver impairment on the PK of Parlodel and its metabolites has not been evaluated.
Since Parlodel is mainly eliminated by metabolism, liver impairment may increase the plasma
levels of bromocriptine, therefore, caution may be necessary (see PRECAUTIONS, general).
The effect of age, race, and gender on the pharmacokinetics of bromocriptine and its metabolites
has not been evaluated.
INDICATIONS AND USAGE
Hyperprolactinemia-Associated Dysfunctions
Parlodel® (bromocriptine mesylate) is indicated for the treatment of dysfunctions associated with
hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or
hypogonadism. Parlodel treatment is indicated in patients with prolactin-secreting adenomas,
which may be the basic underlying endocrinopathy contributing to the above clinical
presentations. Reduction in tumor size has been demonstrated in both male and female patients
with macroadenomas. In cases where adenectomy is elected, a course of Parlodel therapy may be
used to reduce the tumor mass prior to surgery.
Acromegaly
Parlodel therapy is indicated in the treatment of acromegaly. Parlodel therapy, alone or as
adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50%
or more in approximately ½ of patients treated, although not usually to normal levels.
Since the effects of external pituitary radiation may not become maximal for several years,
adjunctive therapy with Parlodel offers potential benefit before the effects of irradiation are
manifested.
Parkinson’s Disease
Parlodel SnapTabs® or capsules are indicated in the treatment of the signs and symptoms of
idiopathic or postencephalitic Parkinson’s disease. As adjunctive treatment to levodopa (alone or
with a peripheral decarboxylase inhibitor), Parlodel therapy may provide additional therapeutic
benefits in those patients who are currently maintained on optimal dosages of levodopa, those
who are beginning to deteriorate (develop tolerance) to levodopa therapy, and those who are
experiencing “end of dose failure’’ on levodopa therapy. Parlodel therapy may permit a reduction
6 Wynalda, M.A., Wienkers, L.C. (1997). Assessment of potential interactions between dopamine receptor agonists and various
human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos; 25:1211-14.
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of the maintenance dose of levodopa and, thus may ameliorate the occurrence and/or severity of
adverse reactions associated with long-term levodopa therapy such as abnormal involuntary
movements (e.g., dyskinesias) and the marked swings in motor function (“on-off’’ phenomenon).
Continued efficacy of Parlodel therapy during treatment of more than 2 years has not been
established.
Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson’s
disease with Parlodel. Studies have shown, however, significantly more adverse reactions
(notably nausea, hallucinations, confusion and hypotension) in Parlodel-treated patients than in
levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for
Parlodel therapy.
CONTRAINDICATIONS
Hypersensitivity to bromocriptine or to any of the excipients of Parlodel® (bromocriptine
mesylate), uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being
treated for hyperprolactinemia, Parlodel should be withdrawn when pregnancy is diagnosed (see
PRECAUTIONS, Hyperprolactinemic States). In the event that Parlodel is reinstituted to control
a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a
patient experiences a hypertensive disorder of pregnancy, the benefit of continuing Parlodel must
be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When
Parlodel is being used to treat acromegaly, prolactinoma, or Parkinson’s disease in patients who
subsequently become pregnant, a decision should be made as to whether the therapy continues to
be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in
those who may experience hypertensive disorders of pregnancy (including eclampsia,
preeclampsia, or pregnancy-induced hypertension) unless withdrawal of Parlodel is considered to
be medically contraindicated.
The drug should not be used during the postpartum period in women with a history of coronary
artery disease and other severe cardiovascular conditions unless withdrawal is considered
medically contraindicated. If the drug is used in the postpartum period, the patient should be
observed with caution.
WARNINGS
Since hyperprolactinemia with amenorrhea/galactorrhea and infertility has been found in patients
with pituitary tumors, a complete evaluation of the pituitary is indicated before treatment with
Parlodel® (bromocriptine mesylate).
If pregnancy occurs during Parlodel administration, careful observation of these patients is
mandatory. Prolactin-secreting adenomas may expand and compression of the optic or other
cranial nerves may occur, emergency pituitary surgery becoming necessary. In most cases, the
compression resolves following delivery. Reinitiation of Parlodel treatment has been reported to
produce improvement in the visual fields of patients in whom nerve compression has occurred
during pregnancy. The safety of Parlodel treatment during pregnancy to the mother and fetus has
not been established.
Parlodel has been associated with somnolence, and episodes of sudden sleep onset, particularly in
patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases
without awareness or warning signs, has been reported. Patients must be informed of this and
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advised not to drive or operate machines during treatment with bromocriptine. Patients who have
experienced somnolence and/or an episode of sudden sleep onset must not drive or operate
machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Symptomatic hypotension can occur in patients treated with Parlodel for any indication. In
postpartum studies with Parlodel, decreases in supine systolic and diastolic pressures of greater
than 20 mm and 10 mm Hg, respectively, have been observed in almost 30% of patients
receiving Parlodel. On occasion, the drop in supine systolic pressure was as much as 50-59 mm
of Hg.
Since, especially during the first days of treatment, hypotensive reactions may occasionally occur
and result in reduced alertness, particular care should be exercised when driving a vehicle or
operating machinery.
While hypotension during the start of therapy with Parlodel occurs in some patients, in rare cases
serious adverse events, including hypertension, myocardial infarction, seizures, stroke, have been
reported in postpartum women treated with Parlodel. Hypertension have been reported,
sometimes at the initiation of therapy, but often developing in the second week of therapy;
seizures have also been reported both with and without the prior development of hypertension;
stroke have been reported mostly in postpartum patients whose prenatal and obstetric courses had
been uncomplicated. Many of these patients experiencing seizures (including cases of status
epilepticus) and/or strokes reported developing a constant and often progressively severe
headache hours to days prior to the acute event. Some cases of strokes and seizures were also
preceded by visual disturbances (blurred vision, and transient cortical blindness). Cases of acute
myocardial infarction have also been reported
Although a causal relationship between Parlodel administration and hypertension, seizures,
strokes, and myocardial infarction in postpartum women has not been established, use of the drug
in patients with uncontrolled hypertension is not recommended. In patients being treated for
hyperprolactinemia, Parlodel should be withdrawn when pregnancy is diagnosed (see
PRECAUTIONS, Hyperprolactinemic States). In the event that Parlodel is reinstituted to control
a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a
patient experiences a hypertensive disorder of pregnancy, the benefit of continuing Parlodel must
be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When
Parlodel is being used to treat acromegaly or Parkinson’s disease in patients who subsequently
become pregnant, a decision should be made as to whether the therapy continues to be medically
necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who
may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or
pregnancy-induced hypertension) unless withdrawal of Parlodel is considered to be medically
contraindicated. Because of the possibility of an interaction between Parlodel and other ergot
alkaloids, the concomitant use of these medications is not recommended. Periodic monitoring of
the blood pressure, particularly during the first weeks of therapy is prudent. If hypertension,
severe, progressive, or unremitting headache (with or without visual disturbance), or evidence of
CNS toxicity develops, drug therapy should be discontinued and the patient should be evaluated
promptly. Particular attention should be paid to patients who have recently been treated or are on
concomitant therapy with drugs that can alter blood pressure. Their concomitant use in the
puerperium is not recommended.
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Among patients on Parlodel, particularly on long-term and high-dose treatment, pleural and
pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have
been reported. Patients with unexplained pleuropulmonary disorders should be examined
thoroughly and discontinuation of Parlodel therapy should be considered. In those instances in
which Parlodel treatment was terminated, the changes slowly reverted towards normal.
In a few patients on Parlodel, particularly on long-term and high-dose treatment, retroperitoneal
fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible
stage it is recommended that its manifestations (e.g., back pain, edema of the lower limbs,
impaired kidney function) should be watched in this category of patients. Parlodel medication
should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.
PRECAUTIONS
General
Safety and efficacy of Parlodel® (bromocriptine mesylate) have not been established in patients
with renal or hepatic disease. Care should be exercised when administering Parlodel therapy
concomitantly with other medications known to lower blood pressure.
The drug should be used with caution in patients with a history of psychosis or cardiovascular
disease. If acromegalic patients or patients with prolactinoma or Parkinson’s disease are being
treated with Parlodel during pregnancy, they should be cautiously observed, particularly during
the postpartum period if they have a history of cardiovascular disease.
Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or
glucose-galactose malabsorption should not take this medicine.
Hyperprolactinemic States
Visual field impairment is a known complication of macroprolactinoma. Effective treatment with
Parlodel leads to a reduction in hyperprolactinemia and often to a resolution of the visual
impairment. In some patients, however, a secondary deterioration of visual fields may
subsequently develop despite normalized prolactin levels and tumor shrinkage, which may result
from traction on the optic chiasm which is pulled down into the now partially empty sella. In
these cases, the visual field defect may improve on reduction of bromocriptine dosage while
there is some elevation of prolactin and some tumor re-expansion. Monitoring of visual fields in
patients with macroprolactinoma is therefore recommended for an early recognition of secondary
field loss due to chiasmal herniation and adaptation of drug dosage.
The relative efficacy of Parlodel versus surgery in preserving visual fields is not known. Patients
with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide
on the most appropriate therapy.
Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients
presenting with amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of
the pituitary is essential to detect the presence of a prolactin-secreting adenoma. Patients not
seeking pregnancy, or those harboring large adenomas, should be advised to use contraceptive
measures, other than oral contraceptives, during treatment with Parlodel. Since pregnancy may
occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks
during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a
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menstrual period. Treatment with Parlodel SnapTabs® or capsules should be discontinued as soon
as pregnancy has been established. Patients must be monitored closely throughout pregnancy for
signs and symptoms that may signal the enlargement of a previously undetected or existing
prolactin-secreting tumor. Discontinuation of Parlodel treatment in patients with known
macroadenomas has been associated with rapid regrowth of tumor and increase in serum
prolactin in most cases.
Cerebrospinal fluid rhinorrhea has been observed in some patients with prolactin-secreting
adenomas treated with Parlodel.
Acromegaly
Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with
Parlodel. The response, should it occur, can be reversed by reducing the dose of Parlodel and
may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from
peptic ulcers have been reported, some fatal. Although there is no evidence that Parlodel
increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic
ulcer should be investigated thoroughly and treated appropriately. Patients with a history of
peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with
Parlodel.
Possible tumor expansion while receiving Parlodel therapy has been reported in a few patients.
Since the natural history of growth hormone-secreting tumors is unknown, all patients should be
carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment
and alternative procedures considered.
Parkinson’s Disease
Safety during long-term use for more than 2 years at the doses required for parkinsonism has not
been established.
As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and
renal function is recommended. Symptomatic hypotension can occur and, therefore, caution
should be exercised when treating patients receiving antihypertensive drugs.
High doses of Parlodel may be associated with confusion and mental disturbances. Since
parkinsonian patients may manifest mild degrees of dementia, caution should be used when
treating such patients.
Parlodel administered alone or concomitantly with levodopa may cause hallucinations (visual or
auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of
Parlodel is required. Rarely, after high doses, hallucinations have persisted for several weeks
following discontinuation of Parlodel.
Postmarketing reports suggest that patients treated with anti-Parkinson medications can
experience intense urges to gamble, increased sexual urges, intense urges to spend money
uncontrollably, and other intense urges. Patients may be unable to control these urges while
taking one or more of the medications that are generally used for the treatment of Parkinson’s
disease and that increase central dopaminergic tone, including Parlodel. In some cases, although
not all, these urges were reported to have stopped when the dose was reduced or the medication
was discontinued. Because patients may not recognize these behaviors as abnormal it is
important for prescribers to specifically ask patients or their caregivers about the development of
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new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being
treated with Parlodel. Physicians should consider dose reduction or stopping the medication if a
patient develops such urges while taking Parlodel.
As with levodopa, caution should be exercised when administering Parlodel to patients with a
history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia.
Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2-10
years) with Parlodel in doses ranging from 30-140 mg daily.
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2
approximately 6-fold higher) of developing melanoma than the general population. Whether the
increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to
treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are
advised to monitor for melanomas frequently and on a regular basis when using Parlodel for any
indication. Ideally, periodic skin examinations should be performed by appropriately qualified
individuals (e.g. dermatologists).
Discontinuation of Parlodel should be undertaken gradually whenever possible, even if the
patient is to remain on L-dopa. A symptom complex resembling the neuroleptic malignant
syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and
autonomic instability), with no other obvious etiology, has been reported in association with
rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
Information for Patients
During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported
early in the course of Parlodel therapy. In postmarketing reports, Parlodel has been associated
with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s
disease. Sudden onset of sleep during daily activities, in some cases without awareness or
warning signs, has been reported very rarely. All patients receiving Parlodel should be cautioned
with regard to engaging in activities requiring rapid and precise responses, such as driving an
automobile or operating machinery. Patients being treated with Parlodel and presenting with
somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities
where impaired alertness may put themselves or others at risk of serious injury or death (e.g.,
operating machines).
Patients receiving Parlodel for hyperprolactinemic states associated with macroadenoma or those
who have had previous transsphenoidal surgery, should be told to report any persistent watery
nasal discharge to their physician. Patients receiving Parlodel for treatment of a macroadenoma
should be told that discontinuation of drug may be associated with rapid regrowth of the tumor
and recurrence of their original symptoms.
Patients and their caregivers should be alerted to the possibility that they may experience intense
urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other
intense urges and the inability to control these urges while taking Parlodel. [See Precautions].
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Especially during the first days of treatment, hypotensive reactions may occasionally occur and
result in reduced alertness, particular care should be exercised when driving a vehicle or
operating machinery .
Drug Interactions
The risk of using Parlodel in combination with other drugs has not been systematically evaluated,
but alcohol may potentiate the side effects of Parlodel. Parlodel may interact with dopamine
antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a
decreased efficacy of Parlodel: phenothiazines, haloperidol, metoclopramide, pimozide.
Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when co
administering drugs which are strong inhibitors of this enzyme (such as azole antimycotics, HIV
protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was
shown to increase the plasma levels of bromocriptine (mean AUC and Cmax values increased
3.7-fold and 4.6-fold, respectively).1 The concomitant treatment of acromegalic patients with
bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine
AUC increased about 38%).4 Concomitant use of Parlodel with other ergot alkaloids is not
recommended. Dose adjustment may be necessary in those cases where high doses of
bromocriptine are being used (such as Parkinson’s disease indication).
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate
equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using
dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in
mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose
administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant
uterine tumors, endometrial and myometrial were found in rats as follows: 0/50 control females,
2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given
44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high
estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of
bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not
present in humans. There is no known correlation between uterine malignancies occurring in
bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice
killed after 74 weeks of treatment did not exhibit evidence of drug-related changes.
Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that
included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster
fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo
treatment, and an in vivo micronucleus test for mutagenic potential in mice.
No mutagenic effects were obtained in any of these tests.
Fertility and reproductive performance in female rats were not influenced adversely by treatment
with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of
lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal
range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21
postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg).
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Pregnancy
Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6-15
postcoitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation.
Three mg/kg given on days 6-15 were without effect on nidation, and did not produce any
anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced
increased prenatal mortality in the form of increased incidence of embryonic resorption. One
anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from
the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of
dams treated during the peri- or postnatal period.
Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with
nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect
nidation. The high dose was approximately 63 times the maximum human dose administered in
controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white
rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal
toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological
potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to
day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at
maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this
anomaly. In the third study conducted with New Zealand white rabbits using an identical
protocol, no cleft palates were produced.
No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring
from 6 monkeys at a dose level of 2 mg/kg.
Information concerning 1276 pregnancies in women taking Parlodel has been collected. In the
majority of cases, Parlodel was discontinued within 8 weeks into pregnancy (mean 28.7 days),
however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose
for all patients was 5.8 mg (range 1-40 mg).
Of these 1276 pregnancies, there were 1088 full-term deliveries (4 stillborn), 145 spontaneous
abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3
hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data
compare favorably with the abortion rate (11%-25%) cited for pregnancies induced by
clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin.
Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation,
their frequency has been estimated to be 15%.
The incidence of birth defects in the population at large ranges from 2%-4.5%. The incidence in
1109 live births from patients receiving bromocriptine is 3.3%.
There is no suggestion that Parlodel contributed to the type or incidence of birth defects in this
group of infants.
Nursing Mothers
Parlodel should not be used during lactation in postpartum women.
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Pediatric Use
The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary
adenomas have been established in patients age 16 to adult. No data are available for
bromocriptine use in pediatric patients under the age of 8 years. A single 8-year-old patient
treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported
without therapeutic response.
The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients
in the age group 11 to under 16 years is supported by evidence from well-controlled trials in
adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years
of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with
bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2
failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated
macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone
and in those who received bromocriptine in combination with surgical treatment and/or pituitary
irradiation.
Safety and effectiveness of bromocriptine in pediatric patients have not been established for any
other indication listed in the INDICATIONS AND USAGE section.
Geriatric Use
Clinical studies for Parlodel did not include sufficient numbers of subjects aged 65 and over to
determine whether the elderly respond differently from younger subjects. However, other
reported clinical experiences, including postmarketing reporting of adverse events, have not
identified differences in response or tolerability between elderly and younger patients. Even
though no variation in efficacy or adverse reaction profile in geriatric patients taking Parlodel has
been observed, greater sensitivity of some elderly individuals cannot be categorically ruled out.
In general, dose selection for an elderly patient should be cautious, starting at the lower end of
the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function,
and of concomitant disease or other drug therapy in this population.
ADVERSE REACTIONS
Adverse Reactions from Clinical Trials
Hyperprolactinemic Indications
The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in
degree. Therapy was discontinued in approximately 5% of patients because of adverse effects.
These in decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%),
fatigue (7%), lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion
(3%), constipation (3%), diarrhea (3%) and drowsiness (3%).
A slight hypotensive effect may accompany Parlodel® (bromocriptine mesylate) treatment. The
occurrence of adverse reactions may be lessened by temporarily reducing dosage to ½ SnapTabs®
tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in
patients receiving Parlodel for treatment of large prolactinomas. This has occurred rarely, usually
only in patients who have received previous transsphenoidal surgery, pituitary radiation, or both,
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and who were receiving Parlodel for tumor recurrence. It may also occur in previously untreated
patients whose tumor extends into the sphenoid sinus.
Acromegaly
The most frequent adverse reactions encountered in acromegalic patients treated with Parlodel
were: nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%),
dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%),
drowsiness/tiredness (3%) and vomiting (2%).
Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding, dizziness,
exacerbation of Raynaud’s syndrome, headache and syncope. Rarely (less than 1%) hair loss,
alcohol potentiation, faintness, lightheadedness, arrhythmia, ventricular tachycardia, decreased
sleep requirement, visual hallucinations, lassitude, shortness of breath, bradycardia, vertigo,
paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia, insomnia, heavy
headedness, reduced tolerance to cold, tingling of ears, facial pallor and muscle cramps have
been reported.
Parkinson’s Disease
In clinical trials in which Parlodel was administered with concomitant reduction in the dose of
levodopa/carbidopa, the most common newly appearing adverse reactions were: nausea,
abnormal involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness,
drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance,
ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo.
Less common adverse reactions which may be encountered include: anorexia, anxiety,
blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia,
epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness,
nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and
rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle
cramps of feet and legs or exacerbation of Raynaud’s syndrome.
Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT,
GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical
significance.
Adverse Reactions from Postmarketing Experience
The following adverse reactions have been reported during postapproval use of Parlodel (All
Indications Combined). Because adverse reactions from spontaneous reports are reported
voluntarily from a population of uncertain size, it is generally not possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
Psychiatric disorders: Confusion, psychomotor agitation/excitation, hallucinations, psychotic
disorders, insomnia, libido increase, hypersexuality.
Nervous system disorders: Headache, drowsiness, dizziness, dyskinaesia, somnolence,
paraesthesia, excess daytime somnolence, sudden onset of sleep.
Eye disorders: Visual disturbance, vision blurred.
Ear and labyrinth disorders: Tinnitus.
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Cardiac disorders: Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia,
arrhythmia, cardiac valve fibrosis.
Vascular disorders: Hypotension, orthostatic hypotension (very rarely leading to syncope),
reversible pallor of fingers and toes induced by cold (especially in patients with history of
Raynaud's phenomenon)
Respiratory, thoracic and mediastinal disorders: Nasal congestion, pleural effusion, pleural
fibrosis, pleurisy, pulmonary fibrosis, dyspnoea.
Gastrointestinal disorders: Nausea, constipation, vomiting, dry mouth, diarrhoea, abdominal
pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal haemorrhage.
Skin and subcutaneous tissue disorders: Allergic skin reactions, hair loss.
Musculoskeletal and connective tissue disorders: Leg cramps.
General disorders and administration site conditions: Fatigue, peripheral edema, a syndrome
resembling Neuroleptic Malignant Syndrome on abrupt withdrawal of Parlodel (See
Precautions).
Adverse Events Observed in Other Conditions
Postpartum Patients (see above Warnings)
In postpartum studies with Parlodel, 23 percent of postpartum patients treated had at least 1 side
effect, but they were generally mild to moderate in degree. Therapy was discontinued in
approximately 3% of patients. The most frequently occurring adverse reactions were: headache
(10%), dizziness (8%), nausea (7%), vomiting (3%), fatigue (1.0%), syncope (0.7%), diarrhea
(0.4%) and cramps (0.4%). Decreases in blood pressure ( 20 mm Hg systolic and 10 mm Hg
diastolic) occurred in 28% of patients at least once during the first 3 postpartum days; these were
usually of a transient nature. Reports of fainting in the puerperium may possibly be related to this
effect. In postmarketing experience in the U.S., serious adverse reactions reported include 72
cases of seizures (including 4 cases of status epilepticus), 30 cases of stroke, and 9 cases of
myocardial infarction among postpartum patients. Seizure cases were not necessarily
accompanied by the development of hypertension. An unremitting and often progressively severe
headache, sometimes accompanied by visual disturbance, often preceded by hours to days many
cases of seizure and/or stroke. Most patients had shown no evidence of any of the hypertensive
disorders of pregnancy including eclampsia, preeclampsia or pregnancy-induced hypertension.
One stroke case was associated with sagittal sinus thrombosis, and another was associated with
cerebral and cerebellar vasculitis. One case of myocardial infarction was associated with
unexplained disseminated intravascular coagulation and a second occurred in conjunction with
use of another ergot alkaloid. The relationship of these adverse reactions to Parlodel
administration has not been established.
In rare cases serious adverse events, including hypertension, myocardial infarction, seizures,
stroke, or psychic disorders have been reported in postpartum women treated with Parlodel. In
some patients the development of seizures or stroke was preceded by severe headache and/or
transient visual disturbances. Although the causal relationship of these events to the drug is
uncertain, periodic monitoring of blood pressure is advisable in postpartum women receiving
Parlodel. If hypertension, severe, progressive, or unremitting headache (with or without visual
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disturbances), or evidence of CNS toxicity develop, the administration of Parlodel should be
discontinued and the patient should be evaluated promptly.
Particular caution is required in patients who have recently been treated or are on concomitant
therapy with drugs that can alter blood pressure, e.g. vasoconstrictors such as sympathomimetics
or ergot alkaloids including ergometrine or methylergometrine and their concomitant use in the
puerperium is not recommended.
OVERDOSAGE
The most commonly reported signs and symptoms associated with acute Parlodel®
(bromocriptine mesylate) overdose are: nausea, vomiting, constipation, diaphoresis, dizziness,
pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations,
and repetitive yawning. The lethal dose has not been established and the drug has a very wide
margin of safety. However, one death occurred in a patient who committed suicide with an
unknown quantity of Parlodel and chloroquine.
Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage,
activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and
output is essential. Hypotension should be treated by placing the patient in the Trendelenburg
position and administering I.V. fluids. If satisfactory relief of hypotension cannot be achieved by
using the above measures to their fullest extent, vasopressors should be considered.
There have been isolated reports of children who accidentally ingested Parlodel. Vomiting,
somnolence and fever were reported as adverse events. Patients recovered either spontaneously
within a few hours or after appropriate management.
DOSAGE AND ADMINISTRATION
General
It is recommended that Parlodel® (bromocriptine mesylate) be taken with food. Patients should
be evaluated frequently during dose escalation to determine the lowest dosage that produces a
therapeutic response.
Hyperprolactinemic Indications
The initial dosage of Parlodel SnapTabs® in adults is ½ to one 2½ mg scored tablet daily. An
additional 2½ mg tablet may be added to the treatment regimen as tolerated every 2-7 days until
an optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5-15 mg daily
in adults studied clinically.
Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is ½ to one
2½ mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic
response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with
prolactin-secreting pituitary adenomas.
In order to reduce the likelihood of prolonged exposure to Parlodel should an unsuspected
pregnancy occur, a mechanical contraceptive should be used in conjunction with Parlodel therapy
until normal ovulatory menstrual cycles have been restored. Contraception may then be
discontinued in patients desiring pregnancy.
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Thereafter, if menstruation does not occur within 3 days of the expected date, Parlodel therapy
should be discontinued and a pregnancy test performed.
Acromegaly
Virtually all acromegalic patients receiving therapeutic benefit from Parlodel also have
reductions in circulating levels of growth hormone. Therefore, periodic assessment of circulating
levels of growth hormone will, in most cases, serve as a guide in determining the therapeutic
potential of Parlodel. If, after a brief trial with Parlodel therapy, no significant reduction in
growth hormone levels has taken place, careful assessment of the clinical features of the disease
should be made, and if no change has occurred, dosage adjustment or discontinuation of therapy
should be considered.
The initial recommended dosage is ½ to one 2½ mg Parlodel SnapTabs tablet on retiring (with
food) for 3 days. An additional ½ to 1 SnapTabs tablet should be added to the treatment regimen
as tolerated every 3-7 days until the patient obtains optimal therapeutic benefit. Patients should
be reevaluated monthly and the dosage adjusted based on reductions of growth hormone or
clinical response. The usual optimal therapeutic dosage range of Parlodel varies from
20-30 mg/day in most patients. The maximal dosage should not exceed 100 mg/day.
Patients treated with pituitary irradiation should be withdrawn from Parlodel therapy on a yearly
basis to assess both the clinical effects of radiation on the disease process as well as the effects of
Parlodel therapy. Usually a 4-8 week withdrawal period is adequate for this purpose. Recurrence
of the signs/symptoms or increases in growth hormone indicate the disease process is still active
and further courses of Parlodel should be considered.
Parkinson’s Disease
The basic principle of Parlodel therapy is to initiate treatment at a low dosage and, on an
individual basis, increase the daily dosage slowly until a maximum therapeutic response is
achieved. The dosage of levodopa during this introductory period should be maintained, if
possible. The initial dose of Parlodel is ½ of a 2½ mg SnapTabs tablet twice daily with meals.
Assessments are advised at 2-week intervals during dosage titration to ensure that the lowest
dosage producing an optimal therapeutic response is not exceeded. If necessary, the dosage may
be increased every 14-28 days by 2½ mg/day with meals. Should it be advisable to reduce the
dosage of levodopa because of adverse reactions, the daily dosage of Parlodel, if increased,
should be accomplished gradually in small (2½ mg) increments.
The safety of Parlodel has not been demonstrated in dosages exceeding 100 mg/day.
HOW SUPPLIED
Parlodel® (bromocriptine mesylate) SnapTabs®
2½ mg
Round, off-white, beveled-edge SnapTabs®, each containing 2½ mg bromocriptine (as the
mesylate). Engraved “PARLODEL 2½’’ on one side and scored on reverse side. Complies with
USP dissolution test 1.
Packages of 30……………………………………………………..NDC 0078-0017-15
Packages of 100……………………………………………………NDC 0078-0017-05
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Parlodel® (bromocriptine mesylate) Capsules
5 mg
Caramel and white capsules, each containing 5 mg bromocriptine (as the mesylate). Imprinted in
red ink “PARLODEL 5 mg’’ on one half and “
’’ on other half.
Packages of 30……………………………………………………..NDC 0078-0102-15
Packages of 100……………………………………………………NDC 0078-0102-05
Store and Dispense
Below 25ºC (77ºF); tight, light-resistant container.
January 2012 company logo
Manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
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|
custom-source
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2025-02-12T13:44:25.544551
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017962s065s068lbl.pdf', 'application_number': 17962, 'submission_type': 'SUPPL ', 'submission_number': 68}
|
11,100
|
Lopressor®
metoprolol tartrate tablets, USP
Rx only
Prescribing Information
DESCRIPTION
Lopressor, metoprolol tartrate USP, is a selective beta1-adrenoreceptor blocking agent, available
as 50- and 100-mg tablets for oral administration. Metoprolol tartrate USP is (±)-1-
(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its
structural formula is
Metoprolol tartrate USP is a white, practically odorless, crystalline powder with a molecular
weight of 684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform,
and in alcohol; slightly soluble in acetone; and insoluble in ether.
Inactive Ingredients: Tablets contain cellulose compounds, colloidal silicon dioxide, D&C Red
No. 30 aluminum lake (50-mg tablets), FD&C Blue No. 2 aluminum lake (100-mg tablets),
lactose, magnesium stearate, polyethylene glycol, propylene glycol, povidone, sodium starch
glycolate, talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action:
Lopressor is a beta1-selective (cardioselective) adrenergic receptor blocker. This preferential
effect is not absolute, however, and at higher plasma concentrations, Lopressor also inhibits
beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Reference ID: 3276452
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Clinical pharmacology studies have demonstrated the beta-blocking activity of metoprolol, as
shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of
systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4)
reduction of reflex orthostatic tachycardia.
Hypertension
The mechanism of the antihypertensive effects of beta-blocking agents has not been fully
elucidated. However, several possible mechanisms have been proposed: (1) competitive
antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading
to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the
periphery; and (3) suppression of renin activity.
Angina Pectoris
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial
contraction, and in blood pressure, Lopressor reduces the oxygen requirements of the heart at any given
level of effort, thus making it useful in the long-term management of angina pectoris.
Myocardial Infarction
The precise mechanism of action of Lopressor in patients with suspected or definite myocardial
infarction is not known.
Pharmacodynamics
Relative beta1 selectivity is demonstrated by the following: (1) In healthy subjects, Lopressor is
unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the
effect of nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating
effects of epinephrine. (2) In asthmatic patients, Lopressor reduces FEV1 and FVC significantly
less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses.
Lopressor has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is
detectable only at doses much greater than required for beta blockade. Animal and human
experiments indicate that Lopressor slows the sinus rate and decreases AV nodal conduction.
Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1
hour after oral administration, and its duration is dose-related. For example, a 50% reduction of
the maximum effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and
6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a
significant reduction in exercise systolic blood pressure was evident at 12 hours. When the drug
was infused over a 10-minute period, in normal volunteers, maximum beta blockade was
achieved at approximately 20 minutes. Equivalent maximal beta-blocking effect is achieved with
oral and intravenous doses in the ratio of approximately 2.5:1.
There is a linear relationship between the log of plasma levels and reduction of exercise heart
rate. However, antihypertensive activity does not appear to be related to plasma levels. Because
of variable plasma levels attained with a given dose and lack of a consistent relationship of
antihypertensive activity to dose, selection of proper dosage requires individual titration.
Reference ID: 3276452
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In several studies of patients with acute myocardial infarction, intravenous followed by oral
administration of Lopressor caused a reduction in heart rate, systolic blood pressure and cardiac
output. Stroke volume, diastolic blood pressure and pulmonary artery end diastolic pressure
remained unchanged.
In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the
oral dose within the range of 50-400 mg. Exercise heart rate and systolic blood pressure are
reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise
capacity and the reduction in left ventricular ischemia are also significantly related to the
logarithm of the oral dose.
Pharmacokinetics
Absorption: The estimated oral bioavailability of immediate release metoprolol is about 50%
because of pre-systemic metabolism which is saturable leading to non-proportionate increase in
the exposure with increased dose.
Distribution: Metoprolol is extensively distributed with a reported volume of distribution of 3.2
to 5.6 L/kg. About 10% of metoprolol in plasma is bound to serum albumin. Metoprolol is known
to cross the placenta and is found in breast milk. Metoprolol is also known to cross the blood
brain barrier following oral administration and CSF concentrations close to that observed in
plasma have been reported. Metoprolol is not a significant P-glycoprotein substrate
Metabolism: Lopressor is primarily metabolized by CYP2D6. Metoprolol is a racemic mixture of
R- and S- enantiomers, and when administered orally, it exhibits stereoselective metabolism that
is dependent on oxidation phenotype. CYP2D6 is absent (poor metabolizers) in about 8% of
Caucasians and about 2% of most other populations. Poor CYP2D6 metabolizers exhibit several-
fold higher plasma concentrations of Lopressor than extensive metabolizers with normal
CYP2D6 activity thereby decreasing Lopressor’s cardioselectivity.
Elimination: Elimination of Lopressor is mainly by biotransformation in the liver. The mean
elimination half-life of metoprolol is 3 to 4 hours; in poor CYP2D6 metabolizers the half-life
may be 7 to 9 hours. Approximately 95% of the dose can be recovered in urine. In most subjects
(extensive metabolizers), less than 5% of an oral dose and less than 10% of an intravenous dose
are excreted as unchanged drug in the urine. In poor metabolizers, up to 30% or 40% of oral or
intravenous doses, respectively, may be excreted unchanged; the rest is excreted by the kidneys
as metabolites that appear to have no beta blocking activity. The renal clearance of the stereo-
isomers does not exhibit stereo-selectivity in renal excretion.
Special populations
Geriatric patients: The geriatric population may show slightly higher plasma concentrations of
metoprolol as a combined result of a decreased metabolism of the drug in elderly population and
a decreased hepatic blood flow. However, this increase is not clinically significant or
therapeutically relevant.
Renal impairment: The systemic availability and half-life of Lopressor in patients with renal
failure do not differ to a clinically significant degree from those in normal subjects.
Hepatic Impairment: Since the drug is primarily eliminated by hepatic metabolism, hepatic
impairment may impact the pharmacokinetics of metoprolol. The elimination half-life of
metoprolol is considerably prolonged, depending on severity (up to 7.2 h).
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Clinical Studies:
Hypertension
In controlled clinical studies, Lopressor has been shown to be an effective antihypertensive agent
when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100-
450 mg daily. In controlled, comparative, clinical studies, Lopressor has been shown to be as
effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, to be
equally effective in supine and standing positions.
Angina Pectoris
In controlled clinical trials, Lopressor, administered two or four times daily, has been shown to be
an effective antianginal agent, reducing the number of angina attacks and increasing exercise
tolerance. The dosage used in these studies ranged from 100-400 mg daily. A controlled,
comparative, clinical trial showed that Lopressor was indistinguishable from propranolol in the
treatment of angina pectoris.
Myocardial Infarction
In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, Lopressor
was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial
infarction.
Patients were randomized and treated as soon as possible after their arrival in the hospital, once
their clinical condition had stabilized and their hemodynamic status had been carefully evaluated.
Subjects were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or
more than minimal basal rales as signs of congestive heart failure. Initial treatment consisted of
intravenous followed by oral administration of Lopressor or placebo, given in a coronary care or
comparable unit. Oral maintenance therapy with Lopressor or placebo was then continued for
3 months. After this double-blind period, all patients were given Lopressor and followed up to
1 year.
The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the
Lopressor- and placebo-treatment groups. Among patients treated with Lopressor, there were
comparable reductions in 3-month mortality for those treated early (≤8 hours) and those in whom
treatment was started later. Significant reductions in the incidence of ventricular fibrillation and
in chest pain following initial intravenous therapy were also observed with Lopressor and were
independent of the interval between onset of symptoms and initiation of therapy.
In this study, patients treated with metoprolol received the drug both very early (intra-venously)
and during a subsequent 3-month period, while placebo patients received no beta-blocker
treatment for this period. The study thus was able to show a benefit from the overall metoprolol
regimen but cannot separate the benefit of very early intravenous treatment from the benefit of
later beta-blocker therapy. Nonetheless, because the overall regimen showed a clear beneficial
effect on survival without evidence of an early adverse effect on survival, one acceptable dosage
regimen is the precise regimen used in the trial. Because the specific benefit of very early
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treatment remains to be defined however, it is also reasonable to administer the drug orally to
patients at a later time as is recommended for certain other beta blockers.
INDICATIONS AND USAGE
Hypertension
Lopressor tablets are indicated for the treatment of hypertension. They may be used alone or in
combination with other antihypertensive agents.
Angina Pectoris
Lopressor is indicated in the long-term treatment of angina pectoris.
Myocardial Infarction
Lopressor tablets are indicated in the treatment of hemodynamically stable patients with definite
or suspected acute myocardial infarction to reduce cardiovascular mortality when used alone or in
conjunction with intravenous Lopressor. Oral Lopressor therapy can be initiated after intravenous
Lopressor therapy or, alternatively, oral treatment can begin within 3 to 10 days of the acute
event (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS).
CONTRAINDICATIONS
Hypertension and Angina
Lopressor is contraindicated in sinus bradycardia, heart block greater than first degree,
cardiogenic shock, and overt cardiac failure (see WARNINGS).
Hypersensitivity to Lopressor and related derivatives, or to any of the excipients; hypersensitivity
to other beta blockers (cross sensitivity between beta blockers can occur).
Sick-sinus syndrome.
Severe peripheral arterial circulatory disorders.
Myocardial Infarction
Lopressor is contraindicated in patients with a heart rate <45 beats/min; second- and third-degree
heart block; significant first-degree heart block (P-R interval ≥0.24 sec); systolic blood pressure
<100 mmHg; or moderate-to-severe cardiac failure (see WARNINGS).
WARNINGS
Heart Failure
Beta blockers, like Lopressor, can cause depression of myocardial contractility and may precipitate heart
failure and cardiogenic shock. If signs or symptoms of heart failure develop, treat the patient according to
recommended guidelines. It may be necessary to lower the dose of Lopressor or to discontinue it.
Ischemic Heart Disease
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Do not abruptly discontinue Lopressor therapy in patients with coronary artery disease. Severe
exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients
with coronary artery disease following the abrupt discontinuation of therapy with beta-blockers. When
discontinuing chronically administered Lopressor, particularly in patients with coronary artery disease, the
dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully
monitored. If angina markedly worsens or acute coronary insufficiency develops, Lopressor administration
should be reinstated promptly, at least temporarily, and other measures appropriate for the management of
unstable angina should be taken. Patients should be warned against interruption or discontinuation of
therapy without the physician’s advice. Because coronary artery disease is common and may be
unrecognized, it may be prudent not to discontinue Lopressor therapy abruptly even in patients treated
only for hypertension.
Use During Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery;
however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of
general anesthesia and surgical procedures.
Bradycardia
Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of
Lopressor. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction
disorders may be at increased risk. Monitor heart rate and rhythm in patients receiving Lopressor. If severe
bradycardia develops, reduce or stop Lopressor.
Exacerbation of Bronchospastic Disease
Patients with bronchospastic disease,should, in general, not receive beta blockers, including Lopressor.
Because of its relative beta1 selectivity, however, Lopressor may be used in patients with bronchospastic
disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1
selectivity is not absolute use the lowest possible dose of Lopressor and consider administering Lopressor
in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma
levels associated with the longer dosing interval (see DOSAGE AND ADMINISTRATION).
Bronchodilators, including beta2 agonists, should be readily available or administered concomitantly.
Diabetes and Hypoglycemia
Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as
dizziness and sweating may not be significantly affected.
Pheochromocytoma
If Lopressor is used in the setting of pheochromocytoma, it should be given in combination with an alpha
blocker, and only after the alpha blocker has been initiated. Administration of beta blockers alone in the
setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the
attenuation of beta-mediated vasodilatation in skeletal muscle.
Thyrotoxicosis
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Lopressor may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Avoid abrupt withdrawal
of beta blockade, which might precipitate a thyroid storm.
PRECAUTIONS
Risk of Anaphylactic Reactions
While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of
allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic.
Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic
reaction.
Information for Patients
Advise patients to take Lopressor regularly and continuously, as directed, with or immediately
following meals. If a dose should be missed, the patient should take only the next scheduled dose
(without doubling it). Patients should not discontinue Lopressor without consulting the physician.
Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks
requiring alertness until the patient’s response to therapy with Lopressor has been determined; (2)
to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist
before any type of surgery that he or she is taking Lopressor.
Drug Interactions
Catecholamine-depleting drugs: Catecholamine-depleting drugs (e.g., reserpine) may have an
additive effect when given with beta-blocking agents or monoamine oxidase (MAO) inhibitors.
Observe patients treated with Lopressor plus a catecholamine depletor for evidence of
hypotension or marked bradycardia, which may produce vertigo, syncope, or postural
hypotension. In addition, possibly significant hypertension may theoretically occur up to 14 days
following discontinuation of the concomitant administration with an irreversible MAO inhibitor.
Digitalis glycosides and beta blockers: Both digitalis glycosides and beta blockers slow
atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of
bradycardia. Monitor heart rate and PR interval.
Calcium channel blockers: Concomitant administration of a beta-adrenergic antagonist with a
calcium channel blocker may produce an additive reduction in myocardial contractility because
of negative chronotropic and inotropic effects.
CYP2D6 Inhibitors: Potent inhibitors of the CYP2D6 enzyme may increase the plasma
concentration of Lopressor which would mimic the pharmacokinetics of CYP2D6 poor
metabolizer (see Pharmacokinetics section). Increase in plasma concentrations of metoprolol
would decrease the cardioselectivity of metoprolol. Known clinically significant potent inhibitors
of CYP2D6 are antidepressants such as fluvoxamine, fluoxetine, paroxetine, sertraline,bupropion,
clomipramine, and desipramine; antipsychotics such as chlorpromazine, fluphenazine,
haloperidol, and thioridazine; antiarrhythmics such as quinidine or propafenone; antiretrovirals
such as ritonavir; antihistamines such as diphenhydramine; antimalarials such as
hydroxychloroquine or quinidine; antifungals such as terbinafine.
Hydralazine: Concomitant administration of hydralazine may inhibit presystemic metabolism of
metoprolol leading to increased concentrations of metoprolol.
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Alpha-adrenergic agents: Antihypertensive effect of alpha-adrenergic blockers such as
guanethidine, betanidine, reserpine, alpha-methyldopa or clonidine may be potentiated by beta-
blockers including Lopressor. Beta- adrenergic blockers may also potentiate the postural
hypotensive effect of the first dose of prazosin, probably by preventing reflex tachycardia. On the
contrary, beta adrenergic blockers may also potentiate the hypertensive response to withdrawal of
clonidine in patients receiving concomitant clonidine and beta-adrenergic blocker. If a patient is
treated with clonidine and Lopressor concurrently, and clonidine treatment is to be discontinued,
stop Lopressor several days before clonidine is withdrawn. Rebound hypertension that can follow
withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.
Ergot alkaloid: Concomitant administration with beta-blockers may enhance the vasoconstrictive
action of ergot alkaloids.
Dipyridamole: In general, administration of a beta-blocker should be withheld before
dipyridamole testing, with careful monitoring of heart rate following the dipyridamole injection.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year
study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the
development of spontaneously occurring benign or malignant neoplasms of any type. The only
histologic changes that appeared to be drug related were an increased incidence of generally mild
focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary
hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to
750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female
mice receiving the highest dose than in untreated control animals. There was no increase in
malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or
malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or
biologically significant differences were observed between treated and control mice of either sex
for any type of tumor.
All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in
somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test
in somatic interphase nuclei) were negative.
Reproduction toxicity studies in mice, rats and rabbits did not indicate teratogenic potential for metoprolol
tartrate. Embryotoxicity and/or fetotoxicity in rats and rabbits were noted starting at doses of 50 mg/kg in
rats and 25 mg/kg in rabbits, as demonstrated by increases in preimplantation loss, decreases in the
number of viable fetuses per dose, and/or decreases in neonatal survival. High doses were associated with
some maternal toxicity, and growth delay of the offspring in utero, which was reflected in minimally
lower weights at birth. The oral NOAELs for embryo-fetal development in mice, rats, and rabbits were
considered to be 25, 200, and 12.5 mg/kg. This corresponds to dose levels that are approximately 0.3, 4,
and 0.5 times, respectively, when based on surface area, the maximum human oral dose (8 mg/kg/day) of
metoprolol tartrate. Metoprolol tartrate has been associated with reversible adverse effects on
spermatogenesis starting at oral dose levels of 3.5 mg/kg in rats (a dose that is only 0.1-times the human
dose, when based on surface area), although other studies have shown no effect of metoprolol tartrate on
reproductive performance in male rats.
Pregnancy Category C
Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.
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Lopressor has been shown to increase postimplantation loss and decrease neonatal survival in rats
at doses up to 11 times the maximum daily human dose of 450 mg, when based on surface area.
Distribution studies in mice confirm exposure of the fetus when Lopressor is administered to the
pregnant animal. These limited animal studies do not indicate direct or indirect harmful effects
with respect to teratogenicity (see Carcinogenesis, Mutagenesis, Impairment of Fertility).
There are no adequate and well-controlled studies in pregnant women. The amount of data on the
use of metoprolol in pregnant women is limited. The risk to the fetus/mother is unknown.
Because animal reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.
Nursing Mothers
Lopressor is excreted in breast milk in a very small quantity. An infant consuming 1 liter of
breast milk daily would receive a dose of less than 1 mg of the drug.
Fertility
The effects of Lopressor on the fertility of human have not been studied.
Lopressor showed effects on spermatogenesis in male rats at a therapeutic dose level, but had no
effect on rates of conception at higher doses in animal fertility studies (see Carcinogenesis,
Mutagenesis, Impairment of Fertility).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical trials of Lopressor in hypertension did not include sufficient numbers of elderly patients
to determine whether patients over 65 years of age differ from younger subjects in their response
to Lopressor. Other reported clinical experience in elderly hypertensive patients has not identified
any difference in response from younger patients.
In worldwide clinical trials of Lopressor in myocardial infarction, where approximately 478
patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety
and effectiveness were found. Other reported clinical experience in myocardial infarction has not
identified differences in response between the elderly and younger patients. However, greater
sensitivity of some elderly individuals taking Lopressor cannot be categorically ruled out.
Therefore, in general, it is recommended that dosing proceed with caution in this population.
ADVERSE REACTIONS
Hypertension and Angina
Most adverse effects have been mild and transient.
Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients.
Depression has been reported in about 5 of 100 patients. Mental confusion and short-term
memory loss have been reported. Headache, nightmares, and insomnia have also been reported.
Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100
patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations;
congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100
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patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also
been reported very rarely. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS.)
Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100
patients (see WARNINGS). Rhinitis has also been reported.
Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric
pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients.
Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of
hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline
phosphatase, and lactic dehydrogenase elevations have also been reported.
Hypersensitive Reactions: Pruritus or rash have occurred in about 5 of 100 patients. Very rarely,
photosensitivity and worsening of psoriasis has been reported.
Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients.
Musculoskeletal pain, blurred vision, and tinnitus have also been reported.
There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes.
Discontinuation of the drug should be considered if any such reaction is not otherwise explicable.
There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis
(relationship to Lopressor has not been definitely established).
The oculomucocutaneous syndrome associated with the beta blocker practolol has not been
reported with Lopressor.
Myocardial Infarction
Central Nervous System: Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep
disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced
libido have also been reported, but a drug relationship is not clear.
Cardiovascular: In the randomized comparison of Lopressor and placebo described in the
CLINICAL PHARMACOLOGY section, the following adverse reactions were reported:
Lopressor®
Placebo
Hypotension (systolic BP <90 mmHg)
27.4%
23.2%
Bradycardia (heart rate <40 beats/min)
15.9%
6.7%
Second- or third-degree heart block
4.7%
4.7%
First-degree heart block (P-R ≥0.26 sec)
5.3%
1.9%
Heart failure
27.5%
29.6%
Respiratory: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients.
Gastrointestinal: Nausea and abdominal pain have been reported in fewer than 1 of 100 patients.
Dermatologic: Rash and worsened psoriasis have been reported, but a drug relationship is not
clear.
Miscellaneous: Unstable diabetes and claudication have been reported, but a drug relationship is
not clear.
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Potential Adverse Reactions
A variety of adverse reactions not listed above have been reported with other beta-adrenergic
blocking agents and should be considered potential adverse reactions to Lopressor.
Central Nervous System: Reversible mental depression progressing to catatonia; an acute
reversible syndrome characterized by disorientation for time and place, short-term memory loss,
emotional lability, slightly clouded sensorium, and decreased performance on
neuropsychometrics.
Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm and
respiratory distress.
Postmarketing Experience
The following adverse reactions have been reported during postapproval use of Lopressor:
confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein
(HDL). Because these reports are from a population of uncertain size and are subject to
confounding factors, it is not possible to reliably estimate their frequency.
OVERDOSAGE
Acute Toxicity
Several cases of overdosage have been reported, some leading to death.
Oral LD 50’s (mg/kg): mice, 1158-2460; rats, 3090-4670.
Signs and Symptoms
Potential signs and symptoms associated with overdosage with Lopressor are bradycardia,
hypotension, bronchospasm, myocardial infarction, cardiac failure and death.
Management
There is no specific antidote.
In general, patients with acute or recent myocardial infarction may be more hemodynamically
unstable than other patients and should be treated accordingly (see WARNINGS, Myocardial
Infarction).
On the basis of the pharmacologic actions of Lopressor, the following general measures should be
employed:
Elimination of the Drug: Gastric lavage should be performed.
Other clinical manifestations of overdose should be managed symptomatically based on modern
methods of intensive care.
Hypotension: Administer a vasopressor, e.g., levarterenol or dopamine.
Bronchospasm: Administer a beta2-stimulating agent and/or a theophylline derivative.
Cardiac Failure: Administer digitalis glycoside and diuretic. In shock resulting from inadequate
cardiac contractility, consider administration of dobutamine, isoproterenol or glucagon.
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DOSAGE AND ADMINISTRATION
Hypertension
Individualize the dosage of Lopressor tablets. Lopressor tablets should be taken with or
immediately following meals.
The usual initial dosage of Lopressor tablets is 100 mg daily in single or divided doses, whether
used alone or added to a diuretic. Increase the dosage at weekly (or longer) intervals until
optimum blood pressure reduction is achieved. In general, the maximum effect of any given
dosage level will be apparent after 1 week of therapy. The effective dosage range of Lopressor
tablets is 100-450 mg per day. Dosages above 450 mg per day have not been studied. While once-
daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower
doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and
larger or more frequent daily doses may be required. This can be evaluated by measuring blood
pressure near the end of the dosing interval to determine whether satisfactory control is being
maintained throughout the day. Beta1 selectivity diminishes as the dose of Lopressor is increased.
Angina Pectoris
The dosage of Lopressor tablets should be individualized. Lopressor tablets should be taken with
or immediately following meals.
The usual initial dosage of Lopressor tablets is 100 mg daily, given in two divided doses.
gradually increase the dosage at weekly intervals until optimum clinical response has been
obtained or there is pronounced slowing of the heart rate. The effective dosage range of
Lopressor tablets is 100-400 mg per day. Dosages above 400 mg per day have not been studied. If
treatment is to be discontinued, gradually decrease the dosage over a period of 1-2 weeks (see
WARNINGS).
Myocardial Infarction
Early Treatment: During the early phase of definite or suspected acute myocardial infarction,
initiate treatment with Lopressor as soon as possible after the patient’s arrival in the hospital.
Such treatment should be initiated in a coronary care or similar unit immediately after the
patient’s hemodynamic condition has stabilized.
Begin treatment in this early phase with the intravenous administration of three bolus injections
of 5 mg of Lopressor each; give the injections at approximately 2-minute intervals. During the
intravenous administration of Lopressor, monitor blood pressure, heart rate, and
electrocardiogram.
In patients who tolerate the full intravenous dose (15 mg), initiate Lopressor tablets, 50 mg every
6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the
maintenance dosage is 100 mg twice daily (see Late Treatment below).
Start patients who appear not to tolerate the full intravenous dose on Lopressor tablets either
25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last
intravenous dose or as soon as their clinical condition allows. In patients with severe intolerance,
discontinue Lopressor (see WARNINGS).
Late Treatment: Start patients with contraindications to treatment during the early phase of
suspected or definite myocardial infarction, patients who appear not to tolerate the full early
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treatment, and patients in whom the physician wishes to delay therapy for any other reason on
Lopressor tablets, 100 mg twice daily, as soon as their clinical condition allows. Continue therapy
for at least 3 months. Although the efficacy of Lopressor beyond 3 months has not been
conclusively established, data from studies with other beta blockers suggest that treatment should
be continued for 1-3 years.
Special populations
Pediatric patients: No pediatric studies have been performed. The safety and efficacy of
Lopressor in pediatric patients have not been established.
Renal impairment: No dose adjustment of Lopressor is required in patients with renal
impairment.
Hepatic impairment: Lopressor blood levels are likely to increase substantially in patients with
hepatic impairment. Therefore, Lopressor should be initiated at low doses with cautious gradual
dose titration according to clinical response.
Geriatric patients (>65 years): In general, use a low initial starting dose in elderly patients given
their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
Method of administration:
For oral treatment, the tablets should be swallowed un-chewed with a glass of water. Lopressor
should always be taken in standardized relation with meals. If the physician asks the patient to
take Lopressor either before breakfast or with breakfast, then the patient should continue taking
Lopressor with the same schedule during the course of therapy.
HOW SUPPLIED
Lopressor® Tablets
metoprolol tartrate tablets, USP
Tablets 50 mg – capsule-shaped, biconvex, pink, scored (imprinted GEIGY on one side and 51
twice on the scored side)
Bottles of 100 ................................................................................................ NDC 30698-458-01
Tablets 100 mg – capsule-shaped, biconvex, light blue, scored (imprinted GEIGY on one side
and 71 twice on the scored side)
Bottles of 100 ................................................................................................ NDC 30698-459-01
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from moisture and heat.
Dispense in tight, light-resistant container (USP).
To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals, LLC at --
9VALIDUS (1-866-982-5438) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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Distributed by:
Validus Pharmaceuticals, LLC
Parsippany, New Jersey 07054
info@validuspharma.com
www.validuspharma.com
1-866-9VALIDUS
© 2013 Validus Pharmaceuticals, LLC
March 2013
462000-01
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This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
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/s/
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MARY R SOUTHWORTH
03/14/2013
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2025-02-12T13:44:25.672405
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017963s068lbl.pdf', 'application_number': 17963, 'submission_type': 'SUPPL ', 'submission_number': 68}
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NDA 17-970/S-049
Page 3
Rev 05-02
SIC XXXXX-XX
WARNING - For Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast
Cancer: Serious and life-threatening events associated with NOLVADEX in the risk reduction setting
(women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and
pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial (see
CLINICAL PHARMACOLOGY-Clinical Studies – Reduction in Breast Cancer Incidence In High Risk
Women). Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1,000
women-years of 2.20 for NOLVADEX vs 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000
women-years of 0.17 for NOLVADEX vs 0.0 for placebo)*. For stroke, the incidence rate per 1,000
women-years was 1.43 for NOLVADEX vs 1.00 for placebo**. For pulmonary embolism, the incidence
rate per 1,000 women-years was 0.75 for NOLVADEX versus 0.25 for placebo**.
Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.
Health care providers should discuss the potential benefits versus the potential risks of these serious events
with women at high risk of breast cancer and women with DCIS considering NOLVADEX to reduce their
risk of developing breast cancer.
The benefits of NOLVADEX outweigh its risks in women already diagnosed with breast cancer.
*Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1 study. See
WARNINGS: Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma.
**See Table 3 under CLINICAL PHARMACOLOGY-Clinical Studies.
DESCRIPTION
NOLVADEX® (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral administration.
NOLVADEX Tablets are available as:
10 mg Tablets. Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of
tamoxifen.
20 mg Tablets. Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of
tamoxifen.
Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.
Chemically, NOLVADEX is the trans-isomer of a triphenylethylene derivative. The chemical name is
(Z)2-[4-(1,2-diphenyl-1-butenyl)
phenoxy]-N,
N-dimethylethanamine
2-hydroxy-1,2,3-
propanetricarboxylate (1:1). The structural and empirical formulas are:
This label may not be the latest approved by FDA.
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NDA 17-970/S-049
Page 4
(C32H37NO8)
Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in water at
37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.
CLINICAL PHARMACOLOGY
NOLVADEX is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test
systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites
in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by
dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors.
In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen
receptor protein.
Absorption and Distribution: Following a single oral dose of 20 mg tamoxifen, an average peak plasma
concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The
decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to
7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20
ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in
average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336
ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma
concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once
daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL),
respectively. After initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4
weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks,
suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10
mg NOLVADEX tablets given twice a day vs. a 20 mg NOLVADEX tablet given once daily, the 20 mg
NOLVADEX tablet was bioequivalent to the 10 mg NOLVADEX tablets.
Metabolism: Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is
the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears
to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of
tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-
450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.
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Page 5
Excretion: Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of
the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the
primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and
unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.
Special Populations: The effects of age, gender and race on the pharmacokinetics of tamoxifen have not
been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of
tamoxifen have not been determined.
Drug-drug Interactions: In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem
competitively inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM,
respectively. The clinical significance of these in vitro studies is unknown.
Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-administered.
Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55%,
respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations.
Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.
Clinical Studies - Metastatic Breast Cancer
Premenopausal Women (NOLVADEX vs. Ablation) - Three prospective, randomized studies (Ingle,
Pritchard, Buchanan) compared NOLVADEX to ovarian ablation (oophorectomy or ovarian irradiation) in
premenopausal women with advanced breast cancer. Although the objective response rate, time to
treatment failure, and survival were similar with both treatments, the limited patient accrual prevented a
demonstration of equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio
for death (NOLVADEX/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73 to
1.37. Elevated serum and plasma estrogens have been observed in premenopausal women receiving
NOLVADEX, but the data from the randomized studies do not suggest an adverse effect of this increase.
A limited number of premenopausal patients with disease progression during NOLVADEX therapy
responded to subsequent ovarian ablation.
Male Breast Cancer - Published results from 122 patients (119 evaluable) and case reports in 16 patients
(13 evaluable) treated with NOLVADEX have shown that NOLVADEX is effective for the palliative
treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to NOLVADEX
which constitutes a 50% objective response rate.
Clinical Studies - Adjuvant Breast Cancer
Overview - The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide
overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995. In 1998,
10-year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant NOLVADEX
using doses of 20-40 mg/day for 1-5+ years. Twenty-five percent of patients received 1 year or less of trial
treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of tumors were
estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER
unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered into trials
comparing NOLVADEX to no adjuvant therapy and 42% were entered into trials comparing NOLVADEX
in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node
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NDA 17-970/S-049
Page 6
positive disease and 46% had node negative disease.
Among women with ER positive or unknown breast cancer and positive nodes who received about 5 years
of treatment, overall survival at 10 years was 61.4% for NOLVADEX vs. 50.5% for control (logrank 2p <
0.00001). The recurrence-free rate at 10 years was 59.7% for NOLVADEX vs. 44.5% for control (logrank
2p<0.00001). Among women with ER positive or unknown breast cancer and negative nodes who received
about 5 years of treatment, overall survival at 10 years was 78.9% for NOLVADEX vs. 73.3% for control
(logrank 2p < 0.00001). The recurrence-free rate at 10 years was 79.2% for NOLVADEX versus 64.3% for
control (logrank 2p<0.00001).
The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER positive
or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of NOLVADEX, the
proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p <
0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend
significant at 2p < 0.00001).
Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in
recurrence was 10% (2p=0.007) for all durations taken together, or 9% (2p=0.02) if contralateral breast
cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years
of NOLVADEX on recurrence and mortality were similar regardless of age and concurrent chemotherapy.
There was no indication that doses greater than 20 mg per day were more effective.
Node Positive - Individual Studies - Two studies (Hubay and NSABP B-09) demonstrated an improved
disease-free survival following radical or modified radical mastectomy in postmenopausal women or
women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when
NOLVADEX was added to adjuvant cytotoxic chemotherapy. In the Hubay study, NOLVADEX was
added to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study,
NOLVADEX was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).
In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to
benefit. In the NSABP B-09 study in women age 50-59 years, only women with both estrogen and
progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically
significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less
than 10 fmol. In women age 60-70 years, there was a trend toward a beneficial effect of NOLVADEX
without any clear relationship to estrogen or progesterone receptor status.
Three prospective studies (ECOG-1178, Toronto, NATO) using NOLVADEX adjuvantly as a single agent
demonstrated an improved disease-free survival following total mastectomy and axillary dissection for
postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The
NATO study also demonstrated an overall survival benefit.
Node Negative - Individual Studies - NSABP B-14, a prospective, double-blind, randomized study,
compared NOLVADEX to placebo in women with axillary node-negative, estrogen-receptor positive (>10
fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary
dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment,
there was a significant improvement in disease-free survival in women receiving NOLVADEX. This
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NDA 17-970/S-049
Page 7
benefit was apparent both in women under age 50 and in women at or beyond age 50.
One additional randomized study (NATO) demonstrated improved disease-free survival for NOLVADEX
compared to no adjuvant therapy following total mastectomy and axillary dissection in postmenopausal
women with axillary node-negative breast cancer. In this study, the benefits of NOLVADEX appeared to
be independent of estrogen receptor status.
Duration of Therapy - In the EBCTCG 1995 overview, the reduction in recurrence and mortality was
greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter
period of therapy.
In the NSABP B-14 trial, in which patients were randomized to NOLVADEX 20 mg/day for 5 years vs.
placebo and were disease-free at the end of this 5-year period were offered rerandomization to an additional
5 years of NOLVADEX or placebo. With 4 years of follow-up after this rerandomization, 92% of the
women that received 5 years of NOLVADEX were alive and disease-free, compared to 86% of the women
scheduled to receive 10 years of NOLVADEX (p=0.003). Overall survivals were 96% and 94%,
respectively (p=0.08). Results of the B-14 study suggest that continuation of therapy beyond 5 years does
not provide additional benefit.
A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of 70% in the
five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR=1.27, 95% CI 0.87-
1.85).
In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant
NOLVADEX 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to be 80% in the
patients in the 5-year tamoxifen group, compared with 74% among corresponding patients in the 2-year
treatment group (p=0.03). Disease-free survival at 10 years was 73% in the 5-year group and 67% in the 2-
year group (p=0.009). Compared with 2 years of tamoxifen treatment, 5 years of treatment resulted in a
slightly greater reduction in the incidence of contralateral breast cancer at 10 years, but this difference was
not statistically significant.
Contralateral Breast Cancer - The incidence of contralateral breast cancer is reduced in breast cancer
patients (premenopausal and postmenopausal) receiving NOLVADEX compared to placebo. Data on
contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis
of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with NOLVADEX
of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the incidence rate of
contralateral breast cancer among women receiving NOLVADEX were 13% (NS), 26% (2p = 0.004) and
47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p = 0.008). The
proportional reductions in the incidence of contralateral breast cancer were independent of age and ER
status of the primary tumor. Treatment with about 5 years of NOLVADEX reduced the annual incidence
rate of contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per
1,000 patients in the tamoxifen group.
In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant NOLVADEX 40 mg/day for 2-5
years, the incidence of second primary breast tumors was reduced 40% (p<0.008) on tamoxifen compared
to control. In the NSABP B-14 trial in which patients were randomized to NOLVADEX 20 mg/day for 5
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NDA 17-970/S-049
Page 8
years vs. placebo, the incidence of second primary breast cancers was also significantly reduced (p<0.01).
In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1000 patients in the placebo
group compared with 5.0 per 1,000 patients in the tamoxifen group, at 10 years after first randomization.
Clinical Studies - Ductal Carcinoma in Situ: NSABP B-24, a double-blind, randomized trial included
women with ductal carcinoma in situ (DCIS). This trial compared the addition of NOLVADEX or placebo
to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to
determine whether 5 years of NOLVADEX therapy (20 mg/day) would reduce the incidence of invasive
breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast.
In this trial 1,804 women were randomized to receive either NOLVADEX or placebo for 5 years: 902
women were randomized to NOLVADEX 10 mg tablets twice a day and 902 women were randomized to
placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median
duration of follow-up was 74 months.
The NOLVADEX and placebo groups were well balanced for baseline demographic and prognostic factors.
Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable,
and were detected by mammography alone. Over 60% of the study population was postmenopausal. In
16% of patients, the margin of the resected specimen was reported as being positive after surgery.
Approximately half of the tumors were reported to contain comedo necrosis.
For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women
assigned to NOLVADEX (44 cases - NOLVADEX, 74 cases - placebo; p=0.004; relative risk (RR)=0.57,
95% CI: 0.39-0.84). No data are available regarding the ER status of the invasive cancers. The stage
distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data
base.
Results are shown in Table 1. For each endpoint the following results are presented: the number of events
and rate per 1,000 women per year for the placebo and NOLVADEX groups; and the relative risk (RR) and
its associated 95% confidence interval (CI) between NOLVADEX and placebo. Relative risks less than 1.0
indicate a benefit of NOLVADEX therapy. The limits of the confidence intervals can be used to assess the
statistical significance of the benefits of NOLVADEX therapy. If the upper limit of the CI is less than 1.0,
then a statistically significant benefit exists.
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Page 9
Table 1 - Major Outcomes of the NSABP B-24 Trial
Type of
Event
Lumpectomy,
radiotherapy, and placebo
Lumpectomy,
radiotherapy, and
Nolvadex
RR
95% CI limits
No. of
events
Rate per 1000
women per
year
No. of
events
Rate per 1000
women per
year
Invasive
breast cancer
(Primary
endpoint)
74
16.73
44
9.60
0.57
0.39 to 0.84
-Ipsilateral
47
10.61
27
5.90
0.56
0.33 to 0.91
-Contralateral
25
5.64
17
3.71
0.66
0.33 to 1.27
-Side
undetermined
2
--
0
--
--
Secondary Endpoints
DCIS
56
12.66
41
8.95
0.71
0.46 to 1.08
-Ipsilateral
46
10.40
38
8.29
0.88
0.51 to 1.25
-Contralateral
10
2.26
3
0.65
0.29
0.05 to 1.13
All Breast
Cancer Events
129
29.16
84
18.34
0.63
0.47 to 0.83
-All ipsilateral
events
96
21.70
65
14.19
0.65
0.47 to 0.91
-All
contralateral
events
37
8.36
20
4.37
0.52
0.29 to 0.92
Deaths
32
28
Uterine
Malignancies1
4
9
Endometrial
Adenocarcinoma1
4
0.57
8
1.15
Uterine Sarcoma1
0
0.0
1
0.14
Second primary
malignancies
(other than
endometrial
and breast)
30
29
Stroke
2
7
Thromboembol
ic events
(DVT, PE)
5
15
1Updated follow-up data (median 8.1 years)
Survival was similar in the placebo and NOLVADEX groups. At 5 years from study entry, survival was
97% for both groups.
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NDA 17-970/S-049
Page 10
Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women
The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-
controlled trial with a primary objective to determine whether 5 years of NOLVADEX therapy (20 mg/day)
would reduce the incidence of invasive breast cancer in women at high risk for the disease (See
INDICATIONS AND USAGE). Secondary objectives included an evaluation of the incidence of
ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be
associated with the use of NOLVADEX, including: endometrial cancer, pulmonary embolus, deep vein
thrombosis, stroke, and cataract formation and surgery (See WARNINGS).
The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years
of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age;
number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of
atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5-year predicted risk of
breast cancer of > 1.67% was required for entry into the trial.
In this trial, 13,388 women of at least 35 years of age were randomized to receive either NOLVADEX or
placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up
data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and
24% of women randomized to NOLVADEX (1,596) completed 5 years of therapy. The demographic
characteristics of women on the trial with follow-up data are shown in Table 2.
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NDA 17-970/S-049
Page 11
Table 2. Demographic Characteristics of Women in the
NSABP P-1 Trial
Characteristic
Placebo
Tamoxifen
#
%
#
%
Age (yrs.)
35-39
184
3
158
2
40-49
2,394
36
2,411
37
50-59
2,011
31
2,019
31
60-69
1,588
24
1,563
24
≥70
393
6
393
6
Age at first live birth(yrs.)
Nulliparous
1,202
18
1,205
18
12-19
915
14
946
15
20-24
2,448
37
2,449
37
25-29
1,399
21
1,367
21
≥30
606
9
577
9
Race
White
6,333
96
6,323
96
Black
109
2
103
2
Other
128
2
118
2
Age at menarche
≥14
1,243
19
1,170
18
12-13
3,610
55
3,610
55
≤11
1,717
26
1,764
27
# of first degree relatives with breast cancer
0
1,584
24
1,525
23
1
3,714
57
3,744
57
2+
1,272
19
1,275
20
Prior Hysterectomy
No
4,173
63.5
4,018
62.4
Yes
2,397
36.5
2,464
37.7
# of previous breast biopsies
0
2,935
45
2,923
45
1
1,833
28
1,850
28
≥2
1,802
27
1,771
27
History of atypical hyperplasia in the breast
No
5,958
91
5,969
91
Yes
612
9
575
9
History of LCIS at entry
No
6,165
94
6,135
94
Yes
405
6
409
6
5-year predicted breast cancer risk (%)
≤2.00
1,646
25
1,626
25
2.01-3.00
2,028
31
2,057
31
3.01-5.00
1,787
27
1,707
26
≥5.01
1,109
17
1,162
18
Total
6,570
100.0
6,544
100.0
Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast
cancer was reduced by 44% among women assigned to NOLVADEX (86 cases-NOLVADEX, 156 cases-
placebo; p<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A reduction in the incidence of breast
cancer was seen in each prospectively specified age group (< 49, 50-59, > 60), in women with or without
LCIS, and in each of the absolute risk levels specified in Table 3. A non-significant decrease in the
incidence of ductal carcinoma in situ (DCIS) was seen (23-NOLVADEX, 35-placebo; RR=0.66; 95% CI:
0.39-1.11).
There was no statistically significant difference in the number of myocardial infarctions, severe angina, or
acute ischemic cardiac events between the two groups (61-NOLVADEX, 59-placebo; RR=1.04, 95% CI:
0.73-1.49).
No overall difference in mortality (53 deaths in NOLVADEX group vs. 65 deaths in placebo group) was
present. No difference in breast cancer-related mortality was observed (4 deaths in NOLVADEX group vs.
5 deaths in placebo group).
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Although there was a non-significant reduction in the number of hip fractures (9 on NOLVADEX, 20 on
placebo) in the NOLVADEX group, the number of wrist fractures was similar in the two treatment groups
(69 on NOLVADEX, 74 on placebo). No information regarding bone mineral density or other markers of
osteoporosis is available.
The risks of NOLVADEX therapy include endometrial cancer, DVT, PE, stroke, cataract formation and
cataract surgery (See Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in
the NOLVADEX group vs. 14 in the placebo group (RR=2.48, 95% CI: 1.27-4.92). Deep vein thrombosis
was observed in 30 women receiving NOLVADEX vs. 19 in women receiving placebo (RR=1.59, 95% CI:
0.86-2.98). Eighteen cases of pulmonary embolism were observed in the NOLVADEX group vs. 6 in the
placebo group (RR=3.01, 95% CI: 1.15-9.27). There were 34 strokes on the NOLVADEX arm and 24 on
the placebo arm (RR=1.42; 95% CI 0.82-2.51). Cataract formation in women without cataracts at baseline
was observed in 540 women taking NOLVADEX vs. 483 women receiving placebo (RR=1.13, 95% CI:
1.00-1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking
NOLVADEX vs. 129 women receiving placebo (RR=1.51, 95% CI 1.21-1.89) (See WARNINGS).
Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results
are presented: the number of events and rate per 1000 women per year for the placebo and NOLVADEX
groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between NOLVADEX
and placebo. Relative risks less than 1.0 indicate a benefit of NOLVADEX therapy. The limits of the
confidence intervals can be used to assess the statistical significance of the benefits or risks of
NOLVADEX therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit
exists.
For most participants, multiple risk factors would have been required for eligibility. This table considers
risk factors individually, regardless of other co-existing risk factors, for women who developed breast
cancer. The 5-year predicted absolute breast cancer risk accounts for multiple risk factors in an individual
and should provide the best estimate of individual benefit (See INDICATIONS AND USAGE).
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NDA 17-970/S-049
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Table 3: Major Outcomes of the NSABP P-1 Trial
# OF EVENTS
RATE/1000 WOMEN/YEAR
95% CI
TYPE OF EVENT
PLACEBO NOLVADEX PLACEBO
NOLVADEX
RR LIMITS
Invasive Breast Cancer
156
86
6.49
3.58
0.56 0.43-0.72
Age <49
59
38
6.34
4.11
0.65 0.43-0.98
Age 50-59
46
25
6.31
3.53
0.56 0.35-0.91
Age ≥60
51
23
7.17
3.22
0.45 0.27-0.74
Risk Factors for Breast Cancer
History, LCIS
No
140
78
6.23
3.51
0.56 0.43-0.74
Yes
16
8
12.73
6.33
0.50 0.21-1.17
History, Atypical Hyperplasia
No
138
84
6.37
3.89
0.61 0.47-0.80
Yes
18
2
8.69
1.05
0.12 0.03-0.52
No. First Degree Relatives
0
32
17
5.97
3.26
0.55 0.30-0.98
1
80
45
5.81
3.31
0.57 0.40-0.82
2
35
18
8.92
4.67
0.52 0.30-0.92
≥3
9
6
13.33
7.58
0.57 0.20-1.59
5-Year Predicted Breast Cancer Risk
(as calculated by the Gail Model)
<2.00%
31
13
5.36
2.26
0.42 0.22-0.81
2.01-3.00%
39
28
5.25
3.83
0.73 0.45-1.18
3.01-5.00%
36
26
5.37
4.06
0.76 0.46-1.26
≥5.00%
50
19
13.15
4.71
0.36 0.21-0.61
DCIS
35
23
1.47
0.97
0.66 0.39-1.11
Fractures (protocol-specified sites)
921
761
3.87
3.20
0.61 0.83-1.12
Hip
20
9
0.84
0.38
0.45 0.18-1.04
Wrist2
74
69
3.11
2.91
0.93 0.67-1.29
Total Ischemic Events
59
61
2.47
2.57
1.04 0.71-1.51
Myocardial Infarction
27
27
1.13
1.13
1.00 0.57-1.78
Fatal
8
7
0.33
0.29
0.88 0.27-2.77
Nonfatal
19
20
0.79
0.84
1.06 0.54-2.09
Angina3
12
12
0.50
0.50
1.00 0.41-2.44
Acute Ischemic Syndrome4
20
22
0.84
0.92
1.11 0.58-2.13
Uterine
Malignancies (among
women with an intact uterus) 10
17
57
Endometrial Adenocarcinoma10
17
53
0.71
2.20
Uterine Sarcoma10
0
4
0.0
0.17
Stroke5
24
34
1.00
1.43
1.42 0.82-2.51
Transient Ischemic Attack
21
18
0.88
0.75
0.86 0.43-1.70
Pulmonary Emboli6
6
18
0.25
0.75
3.01 1.15-9.27
Deep-Vein Thrombosis7
19
30
0.79
1.26
1.59 0.86-2.98
Cataracts Developing on Study8
483
540
22.51
25.41
1.13 1.00-1.28
Underwent Cataract Surgery8
63
101
21.83
4.57
1.62 1.18-2.22
Underwent Cataract Surgery9
129
201
5.44
8.56
1.58 1.26-1.97
1Two women had hip and wrist fractures
2 Includes Colles' and other lower radius fractures
3Requiring angioplasty or CABG
4New Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring hospitalization without surgery
5Seven cases were fatal; three in the placebo group and four in the NOLVADEX group
6Three cases in the NOLVADEX group were fatal
7All but three cases in each group required hospitalization
8Based on women without cataracts at baseline (6,230-Placebo, 6,199-NOLVADEX)
9All women (6,707-Placebo, 6,681-NOLVADEX)
10Updated long-term follow-up data (median 6.9 years) added after cut-off for the other information in this table.
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Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes tumor size,
nodal status, ER status. NOLVADEX decreased the incidence of small estrogen receptor positive tumors,
but did not alter the incidence of estrogen receptor negative tumors or larger tumors.
Table 4: Characteristics of Breast Cancer in NSABP P-1 Trial
Staging Parameter
Placebo
Tamoxifen
Total
N=156
N=86
N=242
Tumor size:
T1
117
60
177
T2
28
20
48
T3
7
3
10
T4
1
2
3
Unknown
3
1
4
Nodal status:
Negative
103
56
159
1-3 positive nodes
29
14
43
≥ 4 positive nodes
10
12
22
Unknown
14
4
18
Stage:
I
88
47
135
II: node negative
15
9
24
II: node positive
33
22
55
III
6
4
10
IV
21
1
3
Unknown
12
3
15
Estrogen receptor:
Positive
115
38
153
Negative
27
36
63
Unknown
14
12
26
1 One participant presented with a suspicious bone scan but did not have documented metastases. She subsequently died of metastatic breast cancer.
Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of tamoxifen in
reducing breast cancer incidence have been reported.
The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35 and 70,
who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or matching placebo for
5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Women
without any specific risk factors for breast cancer were to be entered. Between 1992 and 1997, 5408
women were randomized. Hormone Replacement Therapy (HRT) was used in 14% of participants. The
trial closed in 1997 due to the large number of dropouts during the first year of treatment (26%). After 46
months of follow-up there were 22 breast cancers in women on placebo and 19 in women on tamoxifen.
Although no decrease in breast cancer incidence was observed, there was a trend for a reduction in breast
cancer among women receiving protocol therapy for at least 1 year (19-placebo, 11- tamoxifen). The small
numbers of participants along with the low level of risk in this otherwise healthy group precluded an
adequate assessment of the effect of tamoxifen in reducing the incidence of breast cancer.
The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT was
begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial was
subsequently extended to a pilot trial to accrue additional participants to further assess the safety of
tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986 and 1996; they were
selected on the basis of a family history of breast cancer. HRT was used in 40% of participants. In this
trial, with a 70-month median follow-up, 34 and 36 breast cancers (8 noninvasive, 4 on each arm) were
observed among women on tamoxifen and placebo, respectively. Patients in this trial were younger than
those in the NSABP P-1 trial and may have been more likely to develop ER (-) tumors, which are unlikely
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Page 15
to be reduced in number by tamoxifen therapy. Although women were selected on the basis of family
history and were thought to have a high risk of breast cancer, few events occurred, reducing the statistical
power of the study. These factors are potential reasons why the RMT may not have provided an adequate
assessment of the effectiveness of tamoxifen in reducing the incidence of breast cancer.
In these trials, an increased number of cases of deep vein thrombosis, pulmonary embolus, stroke, and
endometrial cancer were observed on the tamoxifen arm compared to the placebo arm. The frequency of
events was consistent with the safety data observed in the NSABP P-1 trial.
INDICATIONS AND USAGE
Metastatic Breast Cancer: NOLVADEX is effective in the treatment of metastatic breast cancer in
women and men. In premenopausal women with metastatic breast cancer, NOLVADEX is an alternative
to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are
estrogen receptor positive are more likely to benefit from NOLVADEX therapy.
Adjuvant Treatment of Breast Cancer: NOLVADEX is indicated for the treatment of node-positive
breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary
dissection, and breast irradiation. In some NOLVADEX adjuvant studies, most of the benefit to date has
been in the subgroup with four or more positive axillary nodes.
NOLVADEX is indicated for the treatment of axillary node-negative breast cancer in women following
total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation.
The estrogen and progesterone receptor values may help to predict whether adjuvant NOLVADEX therapy
is likely to be beneficial.
NOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant
NOLVADEX therapy for breast cancer.
Ductal Carcinoma in Situ (DCIS): In women with DCIS, following breast surgery and radiation,
NOLVADEX is indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the
beginning of the label). The decision regarding therapy with NOLVADEX for the reduction in breast
cancer incidence should be based upon an individual assessment of the benefits and risks of NOLVADEX
therapy.
Current data from clinical trials support five years of adjuvant NOLVADEX therapy for patients with
breast cancer.
Reduction in Breast Cancer Incidence in High Risk Women: NOLVADEX is indicated to reduce the
incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5
years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants
received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of
tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the
label).
NOLVADEX is indicated only for high-risk women. “High risk” is defined as women at least 35 years of
age with a 5-year predicted risk of breast cancer > 1.67%, as calculated by the Gail Model.
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Examples of combinations of factors predicting a 5-year risk > 1.67% are:
Age 35 or older and any of the following combination of factors:
• One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a
breast biopsy showing atypical hyperplasia; or
• At least 2 first degree relatives with a history of breast cancer, and a personal history of at least one
breast biopsy; or
• LCIS
Age 40 or older and any of the following combination of factors:
• One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth
25 or older, and age at menarche 11 or younger; or
• At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger;
or
• One first degree relative with a history of breast cancer, and a personal history of a breast biopsy
showing atypical hyperplasia.
Age 45 or older and any of the following combination of factors:
• At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger;
or
• One first degree relative with a history of breast cancer with a personal history of a benign breast
biopsy, age at menarche 11 or less and age at first live birth 20 or more.
Age 50 or older and any of the following combination of factors:
• At least 2 first degree relatives with a history of breast cancer; or
• History of one breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age
at menarche 11 or less; or
• History of at least two breast biopsies with a history of atypical hyperplasia, and age at first live birth
30 or more.
Age 55 or older and any of the following combination of factors:
• One first degree relative with a history of breast cancer with a personal history of a benign breast
biopsy, and age at menarche 11 or less; or
• History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20
or older.
Age 60 or older and:
• 5-year predicted risk of breast cancer > 1.67%, as calculated by the Gail Model.
For women whose risk factors are not described in the above examples, the Gail Model is necessary to
estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment
Tool by dialing 1-800-544-2007.
There are no data available regarding the effect of NOLVADEX on breast cancer incidence in women with
inherited mutations (BRCA1, BRCA2).
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After an assessment of the risk of developing breast cancer, the decision regarding therapy with
NOLVADEX for the reduction in breast cancer incidence should be based upon an individual assessment
of the benefits and risks of NOLVADEX therapy. In the NSABP P-1 trial, NOLVADEX treatment lowered
the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast
cancer risk (See Table 3 in CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS
NOLVADEX is contraindicated in patients with known hypersensitivity to the drug or any of its
ingredients.
Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS: NOLVADEX is
contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with
a history of deep vein thrombosis or pulmonary embolus.
WARNINGS
Effects in Metastatic Breast Cancer Patients: As with other additive hormonal therapy (estrogens and
androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a
few weeks of starting treatment with NOLVADEX. If hypercalcemia does occur, appropriate measures
should be taken and, if severe, NOLVADEX should be discontinued.
Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma: An increased incidence of uterine
malignancies has been reported in association with NOLVADEX treatment. The underlying mechanism is
unknown, but may be related to the estrogen-like effect of NOLVADEX. Most uterine malignancies seen
in association with NOLVADEX are classified as adenocarcinoma of the endometrium. However, rare
uterine sarcomas, including malignant mixed mullerian tumors, have also been reported. Uterine sarcoma
is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter
survival. Uterine sarcoma has been reported to occur more frequently among long-term users (> 2 years) of
NOLVADEX than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine
sarcoma) have been fatal.
In the NSABP P-1 trial, among participants randomized to NOLVADEX there was a statistically
significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer,
compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI: 1.27-4.92). The 33
cases in participants receiving NOLVADEX were FIGO Stage I, including 20 IA, 12 IB, and 1 IC
endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5
IB) and 1 was FIGO Stage IV. Five women on Nolvadex and 1 on placebo received postoperative radiation
therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age
at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among
participants randomized to placebo (RR=4.50, 95% CI: 1.78-13.16). Among women ≤ 49 years of age at
the time of randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among
participants randomized to placebo (RR=0.94, 95% CI: 0.28-2.89). If age at the time of diagnosis is
considered, there were 4 cases of endometrial cancer among participants < 49 randomized to NOLVADEX
compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-12.0). For women > 50
at the time of diagnosis, there were 29 cases among participants randomized to NOLVADEX compared to
12 among women on placebo (RR=2.5, 95% CI: 1.3-4.9). The risk ratios were similar in the two groups,
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although fewer events occurred in younger women. Most (29 of 33 cases in the NOLVADEX group)
endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the NOLVADEX
group occurred in asymptomatic women. Among women receiving NOLVADEX the events appeared
between 1 and 61 months (average=32 months) from the start of treatment.
In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded
follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial,
the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking
NOLVADEX. Endometrial adenocarcinoma was reported in 53 women randomized to NOLVADEX (52
cases of FIGO Stage I, and 1 Stage III endometrial adenocarcinoma) and 17 women randomized to placebo
(16 cases of FIGO Stage I and 1 case of FIGO Stage II endometrial adenocarcinoma) (incidence per 1,000
women-years of 2.20 and 0.71, respectively). Some patients received post-operative radiation therapy in
addition to surgery. Uterine sarcomas were reported in 4 women randomized to NOLVADEX (2 FIGO I, 1
FIGO II, 1 FIGO III. The FIGO I cases were a sarcoma and a MMMT. The FIGO II was a MMMT and the
FIGO III was a sarcoma) and 0 patients randomized to placebo (incidence per 1,000 women-years of 0.17
and 0.0, respectively). A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma
was observed among women receiving NOLVADEX in five other NSABP clinical trials.
Any patient receiving or who has previously received NOLVADEX who reports abnormal vaginal
bleeding should be promptly evaluated. Patients receiving or who have previously received
NOLVADEX should have annual gynecological examinations and they should promptly inform their
physicians if they experience any abnormal gynecological symptoms, eg, menstrual irregularities,
abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure.
In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to
women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for
women with an intact uterus. There are no data to suggest that routine endometrial sampling in
asymptomatic women taking NOLVADEX to reduce the incidence of breast cancer would be beneficial.
Non-Malignant Effects on the Uterus: An increased incidence of endometrial changes including
hyperplasia and polyps have been reported in association with NOLVADEX treatment. The incidence and
pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of
NOLVADEX.
There have been a few reports of endometriosis and uterine fibroids in women receiving NOLVADEX.
The underlying mechanism may be due to the partial estrogenic effect of NOLVADEX. Ovarian cysts
have also been observed in a small number of premenopausal patients with advanced breast cancer who
have been treated with NOLVADEX.
NOLVADEX has been reported to cause menstrual irregularity or amenorrhea.
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Thromboembolic Effects of NOLVADEX: There is evidence of an increased incidence of
thromboembolic events, including deep vein thrombosis and pulmonary embolism, during NOLVADEX
therapy. When NOLVADEX is coadminstered with chemotherapy, there may be a further increase in the
incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of
NOLVADEX should be carefully considered in women with a history of thromboembolic events.
Data from the NSABP P-1 trial show that participants receiving NOLVADEX without a history of
pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-NOLVADEX, 6-
placebo, RR=3.01, 95% CI: 1.15- 9.27). Three of the pulmonary emboli, all in the NOLVADEX arm, were
fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age
at randomization. Among women receiving NOLVADEX, the events appeared between 2 and 60 months
(average=27 months) from the start of treatment.
In this same population, a non-statistically significant increase in deep vein thrombosis (DVT) was seen in
the NOLVADEX group (30-NOLVADEX, 19-placebo; RR=1.59, 95% CI: 0.86-2.98). The same increase
in relative risk was seen in women < 49 and in women > 50, although fewer events occurred in younger
women. Women with thromboembolic events were at risk for a second related event (7 out of 25 women
on placebo, 5 out of 48 women on NOLVADEX) and were at risk for complications of the event and its
treatment (0/25 on placebo, 4/48 on NOLVADEX). Among women receiving NOLVADEX, deep vein
thrombosis events occurred between 2 and 57 months (average=19 months) from the start of treatment.
There was a non-statistically significant increase in stroke among patients randomized to NOLVADEX
(24-Placebo; 34-NOLVADEX; RR=1.42; 95% CI 0.82-2.51). Six of the 24 strokes in the placebo group
were considered hemorrhagic in origin and 10 of the 34 strokes in the NOLVADEX group were
categorized as hemorrhagic. Seventeen of the 34 strokes in the NOLVADEX group were considered
occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm
were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the placebo
group and 4 strokes in the NOLVADEX group were fatal. Eighty-eight percent of the strokes occurred in
women at least 50 years of age at the time of randomization. Among women receiving NOLVADEX, the
events occurred between 1 and 63 months (average=30 months) from the start of treatment.
Effects on the liver: Liver cancer: In the Swedish trial using adjuvant NOLVADEX 40 mg/day for 2-5
years, 3 cases of liver cancer have been reported in the NOLVADEX-treated group vs. 1 case in the
observation group (See PRECAUTIONS-Carcinogenesis). In other clinical trials evaluating
NOLVADEX, no cases of liver cancer have been reported to date.
One case of liver cancer was reported in NSABP P-1 in a participant randomized to NOLVADEX.
Effects on the liver: Non-malignant effects: NOLVADEX has been associated with changes in liver
enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver,
cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most
reported cases the relationship to NOLVADEX is uncertain. However, some positive rechallenges and
dechallenges have been reported.
In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin, alkaline
phosphatase) were observed (10 on placebo and 6 on NOLVADEX). Serum lipids were not systematically
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collected.
Other cancers: A number of second primary tumors, occurring at sites other than the endometrium, have
been reported following the treatment of breast cancer with NOLVADEX in clinical trials. Data from the
NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving
NOLVADEX. Whether an increased risk for other (non-uterine) cancers is associated with NOLVADEX is
still uncertain and continues to be evaluated.
Effects on the Eye: Ocular disturbances, including corneal changes, decrement in color vision perception,
retinal vein thrombosis, and retinopathy have been reported in patients receiving NOLVADEX. An
increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving
NOLVADEX.
In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those
women without cataracts at baseline (540-NOLVADEX; 483-placebo; RR=1.13, 95% CI: 1.00-1.28) was
observed. Among these same women, NOLVADEX was associated with an increased risk of having
cataract surgery (101-NOLVADEX; 63-placebo; RR=1.62, 95% CI 1.17-2.25) (See Table 3 in
CLINICAL PHARMACOLOGY). Among all women on the trial (with or without cataracts at baseline),
NOLVADEX was associated with an increased risk of having cataract surgery (201-NOLVADEX; 129-
placebo; RR=1.51, 95% CI 1.21-1.89). Eye examinations were not required during the study. No other
conclusions regarding non-cataract ophthalmic events can be made.
Pregnancy Category D: NOLVADEX may cause fetal harm when administered to a pregnant woman.
Women should be advised not to become pregnant while taking NOLVADEX or within 2 months of
discontinuing NOLVADEX and should use barrier or nonhormonal contraceptive measures if sexually
active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on
reproductive functions are expected from the antiestrogenic properties of the drug. In reproductive studies
in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes
were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in
rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a
higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in
some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10
mg/kg/day (about 2-fold the daily maximum recommended human dose on a mg/m2 basis) during
organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high
enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of
teratogenic malformations.
In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4-fold the daily
maximum recommended human dose on a mg/m2 basis) caused changes in both sexes that are similar to
those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these
changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young
women who were exposed to diethylstilbestrol in utero and who have a 1 in 1000 risk of developing clear-
cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown
to cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in young women.
However, only a small number of young women have been exposed to tamoxifen in utero, and a smaller
number have been followed long enough (to age 15-20) to determine whether vaginal or cervical neoplasia
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could occur as a result of this exposure.
There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a small
number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant
women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, or
within approximately two months after discontinuing therapy, the patient should be apprised of the
potential risks to the fetus including the potential long-term risk of a DES-like syndrome.
Reduction in Breast Cancer Incidence in High Risk Women - Pregnancy Category D: For sexually
active women of child-bearing potential, NOLVADEX therapy should be initiated during menstruation. In
women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is
sufficient (See PRECAUTIONS-Information for Patients - Reduction in Breast Cancer Incidence in
High Risk Women).
PRECAUTIONS
General: Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been
occasionally reported in patients taking NOLVADEX for breast cancer. In patients with significant
thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to
NOLVADEX therapy. Leukopenia has been observed, sometimes in association with anemia and/or
thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving
NOLVADEX; this can sometimes be severe.
In the NSABP P-1 trial, 6 women on NOLVADEX and 2 on placebo experienced grade 3-4 drops in
platelet counts (≤50,000/mm3).
Information for Patients:
Reduction in Invasive Breast Cancer and DCIS in Women with DCIS: Women with DCIS treated with
lumpectomy and radiation therapy who are considering NOLVADEX to reduce the incidence of a second
breast cancer event should assess the risks and benefits of therapy, since treatment with NOLVADEX
decreased the incidence of invasive breast cancer, but has not been shown to affect survival (See Table 1 in
CLINICAL PHARMACOLOGY).
Reduction in Breast Cancer Incidence in High Risk Women: Women who are at high risk for breast
cancer can consider taking NOLVADEX therapy to reduce the incidence of breast cancer. Whether the
benefits of treatment are considered to outweigh the risks depends on a woman's personal health history
and on how she weighs the benefits and risks. NOLVADEX therapy to reduce the incidence of breast
cancer may therefore not be appropriate for all women at high risk for breast cancer. Women who are
considering NOLVADEX therapy should consult their health care professional for an assessment of the
potential benefits and risks prior to starting therapy for reduction in breast cancer incidence (See Table 3
in CLINICAL PHARMACOLOGY). Women should understand that NOLVADEX reduces the
incidence of breast cancer, but may not eliminate risk. NOLVADEX decreased the incidence of small
estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or
larger tumors. In women with breast cancer who are at high risk of developing a second breast cancer,
treatment with about 5 years of NOLVADEX reduced the annual incidence rate of a second breast cancer
by approximately 50%.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-049
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Women who are pregnant or who plan to become pregnant should not take NOLVADEX to reduce her risk
of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking
NOLVADEX and for approximately two months after discontinuing therapy if they are sexually active.
Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active
women of child-bearing potential, NOLVADEX therapy should be initiated during menstruation. In
women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is
sufficient (See WARNINGS-Pregnancy Category D).
Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no
difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies
had trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled
women at a lower risk for breast cancer than those in P-1.
Monitoring During NOLVADEX Therapy: Women taking or having previously taken NOLVADEX
should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding, gynecologic
symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of
leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women should inform
all care providers, regardless of the reason for evaluation, that they take NOLVADEX.
Women taking NOLVADEX to reduce the incidence of breast cancer should have a breast examination, a
mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be
repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking
NOLVADEX as adjuvant breast cancer therapy should follow the same monitoring procedures as for
women taking NOLVADEX for the reduction in the incidence of breast cancer. Women taking
NOLVADEX as treatment for metastatic breast cancer should review this monitoring plan with their care
provider and select the appropriate modalities and schedule of evaluation.
Laboratory Tests: Periodic complete blood counts, including platelet counts, and periodic liver function
tests should be obtained.
Drug Interactions: When NOLVADEX is used in combination with coumarin-type anticoagulants, a
significant increase in anticoagulant effect may occur. Where such coadministration exists, careful
monitoring of the patient's prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible
for participation in the trial (See CONTRAINDICATIONS).
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in
combination with NOLVADEX.
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NDA 17-970/S-049
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Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and
excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed
function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma
concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide.
Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions
occur; other CYP3A4 inducing agents have not been studied to confirm this effect.
One patient receiving NOLVADEX with concomitant phenobarbital exhibited a steady state serum level of
tamoxifen lower than that observed for other patients (ie, 26 ng/mL vs. mean value of 122 ng/mL).
However, the clinical significance of this finding is not known. Rifampin induced the metabolism of
tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients.
Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations.
Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl
tamoxifen.
Drug/Laboratory Testing Interactions: During postmarketing surveillance, T4 elevations were reported
for a few postmenopausal patients which may be explained by increases in thyroid-binding globulin. These
elevations were not accompanied by clinical hyperthyroidism.
Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap
smears have been infrequently seen in postmenopausal patients given NOLVADEX.
In the postmarketing experience with NOLVADEX, infrequent cases of hyperlipidemias have been
reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with
pre-existing hyperlipidemias (See ADVERSE REACTIONS-Postmarketing experience section).
Carcinogenesis: A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about
one, three and seven-fold the daily maximum recommended human dose on a mg/m2 basis) administered
by oral gavage for up to 2 years revealed a significant increase in hepatocellular carcinoma at all doses.
The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/kg/day (69%)
compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen
at 45 mg/kg/day (about nine-fold the daily maximum recommended human dose on a mg/m2 basis);
hepatocellular neoplasia was exhibited at 3 to 6 months.
Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two separate mouse
studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at
doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the daily recommended human dose on
a mg/m2 basis).
Mutagenesis: No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with
pro- and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA
adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes.
Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human
lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human
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MCL-5 cells.
Impairment of Fertility: Tamoxifen produced impairment of fertility and conception in female rats at
doses of 0.04 mg/kg/day (about 0.01-fold the daily maximum recommended human dose on a mg/m2 basis)
when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and
reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also increased at
doses of 0.16 mg/kg/day (about 0.03-fold the daily maximum recommended human dose on a mg/m2 basis)
when female rats were dosed from days 7-17 of pregnancy. Tamoxifen produced abortion, premature
delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05-
fold the daily maximum recommended human dose on a mg/m2 basis). There were no teratogenic changes
in either rats or rabbits.
Pregnancy Category D: See WARNINGS.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse reactions in nursing infants from
NOLVADEX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
Pediatric Use: The safety and efficacy of NOLVADEX in pediatric patients have not been established.
Geriatric Use: In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%.
Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer
incidence was seen among participants in each of the subsets: A total of 28 and 10 invasive breast cancers
were seen among participants 65 and older in the placebo and NOLVADEX groups, respectively. Across
all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50
years of age. No overall differences in tolerability were observed between older and younger patients (See
CLINICAL PHARMACOLOGY - Clinical Studies - Reduction in Breast Cancer Incidence in High
Risk Women section).
In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70
years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen
among participants 65 and older in the placebo and NOLVADEX groups, respectively. This subset is too
small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were
comparable to those of younger women enrolled in this trial. No overall differences in tolerability were
observed between older and younger patients.
ADVERSE REACTIONS
Adverse reactions to NOLVADEX are relatively mild and rarely severe enough to require discontinuation
of treatment in breast cancer patients.
Continued clinical studies have resulted in further information which better indicates the incidence of
adverse reactions with NOLVADEX as compared to placebo.
Metastatic Breast Cancer: Increased bone and tumor pain and, also, local disease flare have occurred,
which are sometimes associated with a good tumor response. Patients with increased bone pain may
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require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of
preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or
the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after
starting NOLVADEX and generally subside rapidly.
In patients treated with NOLVADEX for metastatic breast cancer, the most frequent adverse reaction to
NOLVADEX is hot flashes.
Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food,
pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/or partial hair loss,
and vaginal dryness.
Premenopausal Women: The following table summarizes the incidence of adverse reactions reported at a
frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared NOLVADEX
therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.
OVARIAN
NOLVADEX
ABLATION
All Effects
All Effects
% of Women
% of Women
Adverse Reactions*
n = 104
n = 100
Flush
33
46
Amenorrhea
16
69
Altered Menses
13
5
Oligomenorrhea
9
1
Bone Pain
6
6
Menstrual Disorder
6
4
Nausea
5
4
Cough/Coughing
4
1
Edema
4
1
Fatigue
4
1
Musculoskeletal Pain
3
0
Pain
3
4
Ovarian Cyst(s)
3
2
Depression
2
2
Abdominal Cramps
1
2
Anorexia
1
2
*Some women had more than one adverse reaction.
Male Breast Cancer: NOLVADEX is well tolerated in males with breast cancer. Reports from the
literature and case reports suggest that the safety profile of NOLVADEX in males is similar to that seen in
women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male
patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels
were elevated. No significant clinical changes were reported.
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NDA 17-970/S-049
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Adjuvant Breast Cancer: In the NSABP B-14 study, women with axillary node-negative breast cancer
were randomized to 5 years of NOLVADEX 20 mg/day or placebo following primary surgery. The
reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse
events more common on NOLVADEX than on placebo. The incidence of hot flashes (64% vs. 48%),
vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with NOLVADEX
compared with placebo. All other adverse effects occurred with similar frequency in the 2 treatment
groups, with the exception of thrombotic events; a higher incidence was seen in NOLVADEX-treated
patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with NOLVADEX who had
thrombotic events died.
NSABP B-14 Study
_________________________________________________________
% of Women
Adverse Effect
NOLVADEX Placebo
(n=1422)
(n=1437)
_________________________________________________________
Hot Flashes
64
48
Fluid Retention
32
30
Vaginal Discharge
30
15
Nausea
26
24
Irregular Menses
25
19
Weight Loss (>5%)
23
18
Skin Changes
19
15
Increased SGOT
5
3
Increased Bilirubin
2
1
Increased Creatinine
2
1
Thrombocytopenia*
2
1
Thrombotic Events
Deep Vein Thrombosis
0.8
0.2
Pulmonary Embolism
0.5
0.2
Superficial Phlebitis
0.4
0.0
_________________________________________________________
*Defined as a platelet count of <100,000/mm3
In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, NOLVADEX or placebo
was administered for 2 years to women following mastectomy. When compared to placebo, NOLVADEX
showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other
adverse reactions was similar in the 2 treatment groups with the exception of thrombocytopenia where the
incidence for NOLVADEX was 10% vs. 3% for placebo, an observation of borderline statistical
significance.
In other adjuvant studies, Toronto and NOLVADEX Adjuvant Trial Organization (NATO), women
received either NOLVADEX or no therapy. In the Toronto study, hot flashes were observed in 29% of
patients for NOLVADEX vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal
bleeding were reported in 2.8% and 2.0% of women, respectively, for NOLVADEX vs. 0.2% for each in
the untreated group.
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Ductal Carcinoma in Situ (DCIS): The type and frequency of adverse events in the NSABP B-24 trial
were consistent with those observed in the other adjuvant trials conducted with NOLVADEX.
Reduction in Breast Cancer Incidence in High Risk Women: In the NSABP P-1 Trial, there was an
increase in five serious adverse effects in the NOLVADEX group: endometrial cancer (33 cases in the
NOLVADEX group vs. 14 in the placebo group); pulmonary embolism (18 cases in the NOLVADEX
group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the NOLVADEX group vs. 19 in the
placebo group); stroke (34 cases in the NOLVADEX group vs. 24 in the placebo group); cataract
formation (540 cases in the NOLVADEX group vs. 483 in the placebo group) and cataract surgery (101
cases in the NOLVADEX group vs. 63 in the placebo group) (See WARNINGS and Table 3 in
CLINICAL PHARMACOLOGY).
The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only adverse
events more common on NOLVADEX than placebo are shown.
NSABP P-1 Trial: All Adverse Events
% of Women
NOLVADEX PLACEBO
N=6681
N=6707
Self Reported Symptoms
N=64411
N=64691
Hot Flashes
80
68
Vaginal Discharges
55
35
Vaginal Bleeding
23
22
Laboratory Abnormalities
N=65202
N=65352
Platelets decreased
0.7
0.3
Adverse Effects
N=64923
N=64843
Other Toxicities
Mood
11.6
10.8
Infection/Sepsis
6.0
5.1
Constipation
4.4
3.2
Alopecia
5.2
4.4
Skin
5.6
4.7
Allergy
2.5
2.1
1Number with Quality of Life Questionnaires
2Number with Treatment Follow-up Forms
3Number with Adverse Drug Reaction Forms
In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving NOLVADEX and placebo therapy,
respectively withdrew from the trial for medical reasons. The following are the medical reasons for
withdrawing from NOLVADEX and placebo therapy, respectively: Hot flashes (3.1% vs. 1.5%) and
Vaginal Discharge (0.5% vs. 0.1%).
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NDA 17-970/S-049
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In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving NOLVADEX and placebo therapy,
respectively withdrew for non-medical reasons.
On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of
women on NOLVADEX. Severe hot flashes occurred in 28% of women on placebo and 45% of women on
NOLVADEX. Vaginal discharge occurred in 35% and 55% of women on placebo and NOLVADEX
respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of
vaginal bleeding between treatment arms.
Postmarketing experience: Less frequently reported adverse reactions are vaginal bleeding, vaginal
discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient
severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema
multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of
hypersensitivity reactions including angioedema have been reported with NOLVADEX therapy. In some
of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in
some cases with pancreatitis, may be associated with the use of NOLVADEX (see PRECAUTIONS-
Drug/Laboratory Testing Interactions section).
OVERDOSAGE
Signs observed at the highest doses following studies to determine LD50 in animals were respiratory
difficulties and convulsions.
Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer patients
which specifically determined the maximum tolerated dose of NOLVADEX in evaluating the use of very
high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia,
unsteady gait and dizziness were noted. These symptoms occurred within 3-5 days of beginning
NOLVADEX and cleared within 2-5 days after stopping therapy. No permanent neurologic toxicity was
noted. One patient experienced a seizure several days after NOLVADEX was discontinued and neurotoxic
symptoms had resolved. The causal relationship of the seizure to NOLVADEX therapy is unknown.
Doses given in these patients were all greater than 400 mg/m2 loading dose, followed by maintenance
doses of 150 mg/m2 of NOLVADEX given twice a day.
In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients were
given doses higher than 250 mg/m2 loading dose, followed by maintenance doses of 80 mg/m2 of
NOLVADEX given twice a day. For a woman with a body surface area of 1.5 m2 the minimal loading
dose and maintenance doses given at which neurological symptoms and QT changes occurred were at least
6 fold higher in respect to the maximum recommended dose.
No specific treatment for overdosage is known; treatment must be symptomatic.
DOSAGE AND ADMINISTRATION
For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than 20 mg per
day should be given in divided doses (morning and evening).
In three single agent adjuvant studies in women, one 10 mg NOLVADEX tablet was administered two
(ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in
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women with node-negative breast cancer, one 10 mg NOLVADEX tablet was given twice a day for at least
5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide
additional benefit (see CLINICAL PHARMACOLOGY). In the EBCTCG 1995 overview, the reduction
in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those
that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg
per day were more effective. Current data from clinical trials support 5 years of adjuvant NOLVADEX
therapy for patients with breast cancer.
Ductal Carcinoma in Situ (DCIS): The recommended dose is NOLVADEX 20 mg daily for 5 years.
Reduction in Breast Cancer Incidence in High Risk Women: The recommended dose is NOLVADEX
20 mg daily for 5 years. There are no data to support the use of NOLVADEX other than for 5 years (See
CLINICAL PHARMACOLOGY-Clinical Studies - Reduction in Breast Cancer Incidence in High
Risk Women).
HOW SUPPLIED
10 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 10 mg of tamoxifen (round,
biconvex, uncoated, white tablet identified with NOLVADEX 600 debossed on one side and a cameo
debossed on the other side) are supplied in bottles of 60 tablets, 180 tablets and 2500 tablets. NDC 0310-
0600.
20 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 20 mg of tamoxifen (round,
biconvex, uncoated, white tablet identified with NOLVADEX 604 debossed on one side and a cameo
debossed on the other side) are supplied in bottles of 30 tablets, 90 tablets and 1250 tablets. NDC 0310-
0604.
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in a well-closed, light-
resistant container.
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Patient Information about
NOLVADEX
(tamoxifen citrate) Tablets
for Breast Cancer Treatment and Reduction in the Incidence of Breast Cancer
Brand Name: NOLVADEX
(Nol ´va dex)
Generic Name: Tamoxifen (ta-MOX-i-fen)
Please read this information carefully before you begin taking NOLVADEX. It is important to read this
information each time your prescription is filled or refilled in case new information is available. This
summary does not tell you everything about NOLVADEX. Your health care professional is the best source
of information about this medicine. You should talk with him or her before you begin taking NOLVADEX
and at regular checkups. In addition, the professional package insert contains more detailed information on
NOLVADEX.
What are the most important things I should know about NOLVADEX?
NOLVADEX has been shown to help women with advanced breast cancer and in clinical trials of over
30,000 women with early breast cancer it has been shown to reduce the risk of recurrence. Also in a trial of
13,000 women at high risk of breast cancer, NOLVADEX reduced the risk of developing the disease.
Like all medicines, NOLVADEX has some side effects. Most are mild and relate to its hormonal mode of
action. For all women NOLVADEX can, however, also increase the risk of some serious and
potentially life-threatening events, including uterine cancer, blood clots, and stroke. Some of these
events have caused death. NOLVADEX can also increase the risk of getting cataracts or of needing
cataract surgery. If you experience symptoms of any of these, tell your doctor immediately (see “What
should I avoid or do while taking NOLVADEX?”).
If you are a woman at high risk for breast cancer or a woman with DCIS considering NOLVADEX
to reduce your risk of developing breast cancer, you should discuss the potential benefits versus the
potential risks of these serious events with your health care provider.
What is NOLVADEX?
• NOLVADEX is a prescription medicine used to reduce the risk of getting breast cancer (in women who
have a high risk of getting breast cancer)
This effect was shown in the Breast Cancer Prevention Trial (BCPT, NSABP P-1), a large study where
over 13,000 women at high risk for breast cancer were to take NOLVADEX or placebo (a pill without
tamoxifen) for 5 years. High risk women were those who were at least 35 years old and had a combination
of risks that made their chances of developing breast cancer greater than 1.67% in the next five years. The
risk factors included early age at first menstrual period, late age at first pregnancy, no pregnancies, close
family members with breast cancer (mother, sister, or daughter), history of previous breast biopsies, or
high-risk changes in the breast seen on a biopsy. Twenty-five percent of the women in the study completed
5 years of treatment, and most women in this study have been followed for about 4 years. The study
showed that NOLVADEX reduced the chance of getting breast cancer by 44%. The longer-term effects of
NOLVADEX on reducing the chance of getting breast cancer are not known.
We do not know whether taking NOLVADEX for 5 years only delays the appearance of cancer, or actually
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decreases the number of tumors that will ever develop since long-term studies have not been completed.
Some women in this study also experienced serious side effects of NOLVADEX. They are described in
detail in the section, What are the possible side effects of NOLVADEX?. Some of these women
experienced complications related to the treatment of these side effects.
The following summary of the major results from the study is intended to be an aid in weighing the
potential benefit of a reduction in risk of breast cancer against the potential risk of serious side effects of
NOLVADEX.
Cases per year out of 1000
women taking NOLVADEX
Cases per year out of 1000
women taking Placebo
Breast Cancer
3.6
6.5
Endometrial Cancer*
2.3
0.9
Blood clot in the lungs
0.8
0.3
Blood clot in the veins
1.3
0.8
Stroke
1.4
1.0
Cataracts
25.4
22.5
Cataract surgery
46.6
31.4
*In women with a uterus.
Two European trials of NOLVADEX in women with a high risk of breast cancer were also conducted.
They showed no difference in the number of breast cancer cases between the women who took tamoxifen
and those who got placebo. These studies had trial designs that differed from that of NSABP P-1, were
smaller than P-1, and enrolled women at a lower risk for breast cancer than those in the P-1 trial.
• In women with DCIS, following breast surgery and radiation, NOLVADEX is indicated to reduce the
risk of invasive breast cancer. The decision regarding therapy with NOLVADEX for the reduction in
breast cancer incidence should be based upon an individual assessment of the benefits and risks of
NOLVADEX therapy.
A trial evaluated the addition of NOLVADEX to lumpectomy and radiation therapy in women with DCIS.
The primary objective was to determine whether 5 years of NOLVADEX therapy would reduce the
incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast. The
incidence of invasive breast cancer was reduced by 43% among women treated with NOLVADEX.
• NOLVADEX is used to reduce the recurrence of breast cancer in women who have had surgery and/or
radiation therapy to treat early breast cancer. NOLVADEX is also used in women with breast cancer
who are at risk of developing a second breast cancer in the opposite breast.
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The Early Breast Cancer Trialists Collaborative Group reviewed the 10-year results of studies of
NOLVADEX for early breast cancer. Treatment with NOLVADEX for about 5 years reduced the risk of
recurrence of breast cancer and improved overall survival. Treatment with about 5 years of NOLVADEX
also reduced the chance of getting a second breast cancer in the opposite breast by approximately 50%, a
result similar to that seen in the NSABP P-1 study.
• NOLVADEX is used to treat advanced breast cancer in women and men.
Three studies compared NOLVADEX to surgery or radiation to the ovaries in premenopausal women with
advanced breast cancer and found that NOLVADEX was similar to surgery or radiation in causing tumor
shrinkage.
Published studies have demonstrated that NOLVADEX is effective for the treatment of advanced breast
cancer in men.
• NOLVADEX is a prescription tablet available in two dosage strengths: 10 mg tablets and 20 mg
tablets. The active ingredient in each tablet is tamoxifen citrate.
How does NOLVADEX work?
NOLVADEX belongs to a group of medicines called antiestrogens. Antiestrogens work by blocking the
effects of the hormone estrogen in the body. Estrogen may cause the growth of some types of breast
tumors. NOLVADEX may block the growth of tumors that respond to estrogen.
Who should not take NOLVADEX?
• You should not take NOLVADEX to reduce the risk of getting breast cancer if you have ever had blood
clots or if you develop blood clots that require medical treatment. However, if you are taking
NOLVADEX for treatment of early or advanced breast cancer, the benefits of NOLVADEX may
outweigh the risks associated with developing new blood clots. Your health care professional can assist
you in deciding whether NOLVADEX is right for you.
• You should not take NOLVADEX to reduce the risk of getting breast cancer if you are taking
medicines to thin your blood (anticoagulants) like warfarin (Coumadin*).
• You should not take NOLVADEX if you plan to become pregnant while taking NOLVADEX or during
the two months after you stop taking it because NOLVADEX may harm your unborn child. You should
see your doctor immediately and stop taking NOLVADEX if you become pregnant while taking the
drug. Please talk with your doctor about birth control recommendations. If you are capable of
becoming pregnant, you should start NOLVADEX during a menstrual period or if you have irregular
periods have a negative pregnancy test before beginning to take NOLVADEX. NOLVADEX does not
prevent pregnancy, even in the presence of menstrual irregularity.
• You should not take NOLVADEX if you are breast feeding.
• You should not take NOLVADEX if you have ever had an allergic reaction to NOLVADEX or
tamoxifen citrate (the chemical name) or any of its ingredients.
• NOLVADEX is not known to reduce the risk of breast cancer in women with changes in breast cancer
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-049
Page 33
genes (BRCA1 or BRCA2).
• You should not take NOLVADEX to decrease the chance of getting breast cancer if you are less than
age 35 because NOLVADEX has not been tested in younger women.
• You should not take NOLVADEX to reduce the risk of breast cancer unless you are at high risk of
getting breast cancer. Certain conditions put women at high risk and it is possible to calculate this risk
for any woman. Breast cancer risk assessment tools to help calculate your risk of breast cancer have
been developed and are available to your health care professional. You should discuss your risks with
your health care professional.
• Children should not take NOLVADEX because treatment for them has not been sufficiently studied.
How should I take NOLVADEX?
• Follow your doctor’s instructions about when and how to take NOLVADEX. Read the label on the
container. If you are unsure or have questions, ask your doctor or pharmacist.
• You will take NOLVADEX differently, depending on your diagnosis.
• For reduction of the risk of breast cancer, the usual dose is 20 mg a day, for five years.
• For treatment of breast cancer in adult women and men, the usual dose is 20-40 mg a day. Take the
tablets once or twice a day depending on the tablet strength prescribed. If your doctor has prescribed a
different dose, do not change it unless he or she tells you to do so. For women with early breast cancer,
NOLVADEX should be taken for 5 years. For women with advanced cancer, NOLVADEX should be
taken until your doctor feels it is no longer indicated.
• Take your medicine each day. You may find it easier to remember to take your medicine if you take it
at the same time each day. If you forget to take a dose, take it as soon as you remember and then take
the next dose as usual.
• Swallow the tablets whole with a drink of water.
• You can take NOLVADEX with or without food.
• Do not stop taking your tablets unless your doctor tells you to do so.
Are there other important factors to consider before taking NOLVADEX?
• Tell your doctor if you have ever had blood clots that required medical treatment.
• Because NOLVADEX may affect how other medicines work, always tell your doctor if you are taking
any other prescription or non-prescription (over-the-counter) medications, particularly if you are taking
warfarin to thin your blood.
• You should not become pregnant when taking NOLVADEX or during the two months after you stop
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-049
Page 34
taking it as NOLVADEX may harm your unborn child. Please contact your doctor for birth control
recommendations. NOLVADEX does not prevent pregnancy, even in the presence of menstrual
irregularity. You should see your doctor immediately if you think you may have become pregnant after
starting to take NOLVADEX.
What should I avoid or do while taking NOLVADEX?
• You should contact your doctor immediately if you notice any of the following symptoms. Some of
these symptoms may suggest that you are experiencing a rare but serious side effect associated with
NOLVADEX (see “What are the possible side effects of NOLVADEX?”).
− new breast lumps
− vaginal bleeding
− changes in your menstrual cycle
− changes in vaginal discharge
− pelvic pain or pressure
− swelling or tenderness in your calf
− unexplained breathlessness (shortness of breath)
− sudden chest pain
− coughing up blood
− changes in your vision
If you see a health care professional who is new to you (an emergency room doctor, another doctor in the
practice), tell him or her that you take NOLVADEX or have previously taken NOLVADEX.
• Because NOLVADEX may affect how other medicines work, always tell your doctor if you are taking
any other prescription or non-prescription (over-the-counter) medicines. Be sure to tell your doctor if
you are taking warfarin (coumadin) to thin your blood.
• You should not become pregnant when taking NOLVADEX or during the two months after you stop
taking it because NOLVADEX may harm your unborn child. You should see your doctor immediately
if you think you may have become pregnant after starting to take NOLVADEX. Please talk with your
doctor about birth control recommendations. If you are taking NOLVADEX to reduce your risk of
getting breast cancer, and you are sexually active, NOLVADEX should be started during your
menstrual period. If you have irregular periods, you should have a negative pregnancy test before you
start NOLVADEX. NOLVADEX does not prevent pregnancy, even in the presence of menstrual
irregularity.
• If you are taking NOLVADEX to reduce your risk of getting breast cancer, you should know that
NOLVADEX does not prevent all breast cancers. While you are taking NOLVADEX and after you
stop taking NOLVADEX and in keeping with your doctor’s recommendation, you should have annual
gynecological check-ups which should include breast exams and mammograms. If breast cancer occurs,
there is no guarantee that it will be detected at an early stage. This is why it is important to continue
with regular check-ups.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-049
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What are the possible side effects of NOLVADEX?
Like many medicines, NOLVADEX causes side effects in most patients. The majority of the side effects
seen with NOLVADEX have been mild and do not usually cause breast cancer patients to stop taking the
medication. In women with breast cancer, withdrawal from NOLVADEX therapy is about 5%.
Approximately 15% of women who took NOLVADEX to reduce the chance of getting breast cancer stopped
treatment because of side effects.
The most common side effects reported with NOLVADEX are: hot flashes; vaginal discharge or
bleeding; and menstrual irregularities (these side effects may be mild or may be a sign of a more
serious side effect). Women may experience hair loss, skin rashes (itching or peeling skin) or
headaches; or inflammation of the lungs, which may have the same symptoms as pneumonia, such as
breathlessness and cough; however, hair loss is uncommon and is usually mild.
A rare but serious side effect of NOLVADEX is a blood clot in the veins. Blood clots stop the flow of
blood and can cause serious medical problems, disability, or death. Women who take NOLVADEX are at
increased risk for developing blood clots in the lungs and legs. Some women may develop more than one
blood clot, even if NOLVADEX is stopped. Women may also have complications from treating the clot,
such as bleeding from thinning the blood too much. Symptoms of a blood clot in the lungs may include
sudden chest pain, shortness of breath or coughing up blood. Symptoms of a blood clot in the legs are pain
or swelling in the calves. A blood clot in the legs may move to the lungs. If you experience any of these
symptoms of a blood clot, contact your doctor immediately.
NOLVADEX increases the chance of having a stroke, which can cause serious medical problems,
disability, or death. If you experience any symptoms of stroke, such as weakness, difficulty walking or
talking, or numbness, contact your doctor immediately.
NOLVADEX increases the chance of changes occurring in the lining (endometrium) or body of your uterus
which can be serious and could include cancer. If you have not had a hysterectomy (removal of the uterus),
it is important for you to contact your doctor immediately if you experience any unusual vaginal discharge,
vaginal bleeding, or menstrual irregularities; or pain or pressure in the pelvis (lower stomach). These may
be caused by changes to the lining (endometrium) or body of your uterus. It is important to bring them to
your doctor’s attention without delay as they can occasionally indicate the start of something more serious
and even life-threatening.
NOLVADEX may cause cataracts or changes to parts of the eye known as the cornea or retina.
NOLVADEX can increase the chance of needing cataract surgery, and can cause blood clots in the veins of
the eye. NOLVADEX can result in difficulty in distinguishing different colors. If you experience any
changes in your vision, tell your doctor immediately.
Rare side effects, which may be serious, include certain liver problems such as jaundice (which may be
seen as yellowing of the whites of the eyes) or hypertriglyceridemia (increased levels of fats in the blood)
sometimes with pancreatitis (pain or tenderness in the upper abdomen). Stop taking NOLVADEX and
contact your doctor immediately if you develop angioedema (swelling of the face, lips, tongue and/or
throat) even if you have been taking tamoxifen for a long time.
If you are a woman receiving NOLVADEX for treatment of advanced breast cancer, and you experience
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-049
Page 36
excessive nausea, vomiting or thirst, tell your doctor immediately. This may mean that there are changes in
the amount of calcium in your blood (hypercalcemia). Your doctor will evaluate this.
In patients with breast cancer, a temporary increase in the size of the tumor may occur and sometimes
results in muscle aches/bone pain and skin redness. This condition may occur shortly after starting
NOLVADEX and may be associated with a good response to treatment.
Many of these side effects happen only rarely. However, you should contact your doctor if you think you
have any of these or any other problems with your NOLVADEX. Some side effects of NOLVADEX may
become apparent soon after starting the drug, but others may first appear at any time during therapy.
This summary does not include all possible side effects with NOLVADEX. It is important to talk to your
health care professional about possible side effects. If you want to read more, ask your doctor or pharmacist
to give you the professional labeling.
How should I store NOLVADEX?
NOLVADEX Tablets should be stored at room temperature (68-77°F). Keep in a well-closed, light-
resistant container. Keep out of the reach of children.
Do not take your tablets after the expiration date on the container. Be sure that any discarded tablets are out
of the reach of children.
This leaflet provides you with a summary of information about NOLVADEX. Medicines are sometimes
prescribed for uses other than those listed. NOLVADEX has been prescribed specifically for you by your
doctor. Do not give your medicine to anyone else, even if they have a similar condition, because it may
harm them.
If you have any questions or concerns, contact your doctor or pharmacist. Your pharmacist also has a
longer leaflet about NOLVADEX written for health care professionals that you can ask to read. For more
information about NOLVADEX or breast cancer, call 1-800-34 LIFE 4.
*Coumadin is a registered trademark of Bristol-Myers Squibb Pharmaceuticals.
AstraZeneca Pharmaceuticals LP
Wilmington, Delaware 19850-5437
Rev 05-13-02 SIC XXXXX-XX
Printed in USA 2002 AstraZeneca Group of Companies
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Richard Pazdur
5/16/02 03:31:08 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17970s37s44s49lbl.pdf', 'application_number': 17970, 'submission_type': 'SUPPL ', 'submission_number': 37}
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Page 3
MEDICATION GUIDE
NOLVADEX (NOLE-vah-dex) Tablets
Generic name: tamoxifen (ta-MOX-I-fen)
Written for women who use NOLVADEX to lower their high chance of getting breast cancer or
who have ductal carcinoma in situ (DCIS)
This Medication Guide discusses only the use of NOLVADEX to lower the chance of getting
breast cancer in high-risk women and in women treated for DCIS.
People taking NOLVADEX to treat breast cancer have different benefits and different decisions
to make than high-risk women or women with ductal carcinoma in situ (DCIS) taking
NOLVADEX to reduce the chance of getting breast cancer. If you already have breast cancer,
talk with your doctor about how the benefits of treating breast cancer with NOLVADEX
compare to the risks that are described in this document.
Why should I read this Medication Guide?
This guide has information to help you decide whether to use NOLVADEX to lower your chance
of getting breast cancer.
You and your doctor should talk about whether the possible benefit of NOLVADEX in
lowering your high chance of getting breast cancer is greater than its possible risks. Your
doctor has a special computer program or hand-held calculator to tell if you are in the high-risk
group. If you have DCIS and have been treated with surgery and radiation therapy, your doctor
may prescribe NOLVADEX to decrease your chance of getting invasive (spreading) breast
cancer.
Read this guide carefully before you start NOLVADEX. It is important to read the information
you get each time you get more medicine. There may be something new. This guide does not
tell you everything about NOLVADEX and does not take the place of talking with your doctor.
Only you and your doctor can determine if NOLVADEX is right for you.
What is the most important information I should know about using
NOLVADEX to reduce the chance of getting breast cancer?
NOLVADEX is a prescription medicine that is like estrogen (female hormone) in some ways and
different in other ways. In the breast, NOLVADEX can block estrogen’s effects. Because it
does this, NOLVADEX may block the growth of breast cancers that need estrogen to grow
(cancers that are estrogen- or progesterone-receptor positive).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-048
Page 4
NOLVADEX can lower the chance of getting breast cancer in women with a higher than normal
chance of getting breast cancer in the next five years (high-risk women) and women with DCIS.
Because high-risk women don’t have cancer yet, it is important to think carefully about
whether the possible benefit of NOLVADEX in lowering the chance of getting breast
cancer is greater than its possible risks.
This Medication Guide reviews the risks and benefits of using NOLVADEX to reduce the
chance of getting breast cancer in high-risk women and women with DCIS. This guide does not
discuss the special benefits and decisions for people who already have breast cancer.
Why do women and men use NOLVADEX?
NOLVADEX has more than one use. NOLVADEX is used:
1. to lower the chance of getting breast cancer in women with a higher than normal chance
of getting breast cancer in the next 5 years (high-risk women).
2. to lower the chance of getting invasive (spreading) breast cancer in women who had
surgery and radiation for ductal carcinoma in situ (DCIS). DCIS means the cancer is
only inside the milk ducts.
3. to treat breast cancer in women after they have finished early treatment. Early treatment
can include surgery, radiation, and chemotherapy. NOLVADEX may keep the cancer
from spreading to others parts of the body. It may also reduce the woman’s chance of
getting a new breast cancer.
4. in women and men, to treat breast cancer that has spread to other parts of the body
(metastatic breast cancer).
This guide talks only about using NOLVADEX to lower the chance of getting breast cancer (#1
and #2 above).
What are the benefits of NOLVADEX to lower the chance of getting breast
cancer in high-risk women and in women treated for DCIS?
A large US study looked at high-risk women and compared the ones who took NOLVADEX
for 5 years with others who took a pill without NOLVADEX (placebo). High-risk women were
defined as women who have a 1.7% or greater chance of getting breast cancer in the next 5 years,
based on a special computer program. In this study:
•••• Out of every 1,000 high-risk women who took a placebo, each year about 7 got breast
cancer.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-048
Page 5
•••• Out of every 1,000 high-risk women who took NOLVADEX, each year about 4 got
breast cancer.
The study showed that on average, high-risk women who took NOLVADEX lowered their
chances of getting breast cancer by 44%, from 7 in 1,000 to 4 in 1,000.
Another US study looked at women with DCIS and compared those who took NOLVADEX for
5 years with others who took a placebo. In this study:
•••• Out of every 1,000 women with DCIS who took placebo, each year about 17 got breast
cancer.
•••• Out of every 1,000 women with DCIS who took NOLVADEX, each year about 10 got
breast cancer.
The study showed that on average, women with DCIS who took NOLVADEX lowered their
chances of getting invasive (spreading) breast cancer by 43%, from 17 in 1,000 to 10 in 1,000.
These studies do not mean that taking NOLVADEX will lower your personal chance of
getting breast cancer. We do not know what the benefits will be for any one woman who takes
NOLVADEX to reduce her chance of getting breast cancer.
What are the risks of NOLVADEX?
In the studies described under “What are the benefits of NOLVADEX?”, the high-risk women
who took NOLVADEX got certain side effects at a higher rate than those who took a placebo.
Some of these side effects can cause death.
In one study, in women who still had their uterus:
•••• Out of every 1,000 women who took a placebo, each year 1 got endometrial cancer
(cancer of the lining of the uterus) and none got uterine sarcoma (cancer of the body of
the uterus).
•••• Out of every 1,000 women who took NOLVADEX, each year 2 got endometrial
cancer and fewer than 1 got uterine sarcoma.
These results show that, on average, in high-risk women who still had their uterus,
NOLVADEX doubled the chance of getting endometrial cancer from 1 in 1,000 to 2 in 1,000,
and it increased the chance of getting uterine sarcoma. This does not mean that taking
NOLVADEX will double your personal chance of getting endometrial cancer or increase
your chance of getting uterine sarcoma. We do not know what this risk will be for any one
woman. The risk is different for women who no longer have their uterus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-048
Page 6
For all women in this study, taking NOLVADEX increased the risk of having a blood clot
in their lungs or veins, or of having a stroke. In some cases, women died from these effects.
NOLVADEX increased the risk of getting cataracts (clouding of the lens of the eye) or
needing cataract surgery. (See “What are the possible side effects of NOLVADEX?” for more
details about side effects.)
What don’t we know about taking NOLVADEX to reduce the chance of
getting breast cancer?
We don’t know:
•••• if NOLVADEX lowers the chance of getting breast cancer in women who have abnormal
breast cancer genes (BRCA1 and BRCA2)
•••• if taking NOLVADEX for 5 years reduces the number of breast cancers a woman will get
in her lifetime or if it only delays some breast cancers
•••• if NOLVADEX helps a woman live longer
•••• the effects of taking NOLVADEX with hormone replacement therapy (HRT), birth
control pills, or androgens (male hormones)
•••• the benefits of taking NOLVADEX if you are less than 35 years old
Studies are being done to learn more about the long-term benefits and risks of using
NOLVADEX to reduce the chance of getting breast cancer.
What are the possible side effects of NOLVADEX?
The most common side effect of NOLVADEX is hot flashes. This is not a sign of a serious
problem.
The next most common side effect is vaginal discharge. If the discharge is bloody, it could be
a sign of a serious problem. [See “Changes in the lining (endometrium) or body of your uterus”
below.]
Less common but serious side effects of NOLVADEX are listed below. These can occur at
any time. Call your doctor right away if you have any signs of side effects listed below:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-048
Page 7
•••• Changes in the lining (endometrium) or body of your uterus. These changes may
mean serious problems are starting, including cancer of the uterus. The signs of changes
in the uterus are:
− Vaginal bleeding or bloody discharge that could be a rusty or brown color. You
should call your doctor even if only a small amount of bleeding occurs.
− Change in your monthly bleeding, such as in the amount or timing of bleeding or
increased clotting.
− Pain or pressure in your pelvis (below your belly button).
•••• Blood clots in your veins or lungs. These can cause serious problems, including death.
You may get clots up to 2-3 months after you stop taking NOLVADEX. The signs of
blood clots are:
− sudden chest pain, shortness of breath, coughing up blood
− pain, tenderness, or swelling in one or both of your legs
•••• Stroke. Stroke can cause serious medical problems, including death. The signs of stroke
are:
− sudden weakness, tingling, or numbness in your face, arm or leg, especially on one
side of your body
− sudden confusion, trouble speaking or understanding
− sudden trouble seeing in one or both eyes
− sudden trouble walking, dizziness, loss of balance or coordination
− sudden severe headache with no known cause
•••• Cataracts or increased chance of needing cataract surgery. The sign of these
problems is slow blurring of your vision.
•••• Liver problems, including jaundice. The signs of liver problems include lack of
appetite and yellowing of your skin or whites of your eyes.
These are not all the possible side effects of NOLVADEX. For a complete list, ask your doctor
or pharmacist.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-048
Page 8
Who should not take NOLVADEX?
Do not take NOLVADEX for any reason if you
•••• Are pregnant or plan to become pregnant while taking NOLVADEX or during the 2
months after you stop taking NOLVADEX. NOLVADEX may harm your unborn
baby. It takes about 2 months to clear NOLVADEX from your body. To be sure you are
not pregnant, you can start taking NOLVADEX while you are having your menstrual
period. Or, you can take a pregnancy test to be sure you are not pregnant before you
begin.
•••• Are breast feeding. We do not know if NOLVADEX can pass through your milk and
harm your baby.
•••• Have had an allergic reaction to NOLVADEX or tamoxifen (the other name for
NOLVADEX), or to any of its inactive ingredients.
If you get pregnant while taking NOLVADEX, stop taking it right away and contact your
doctor. NOLVADEX may harm your unborn baby.
Do not take NOLVADEX to lower your chance of getting breast cancer if:
•••• You ever had a blood clot that needed medical treatment.
•••• You are taking medicines to thin your blood, like warfarin, (also called Coumadin®*).
•••• Your ability to move around is limited for most of your waking hours.
•••• You are at risk for blood clots. Your doctor can tell you if you are at high risk for blood
clots.
•••• You do not have a higher than normal chance of getting breast cancer. Your doctor can
tell you if you are a high-risk woman.
How should I take NOLVADEX?
•••• Swallow the tablet(s) whole, with water or another non-alcoholic liquid. You can take
NOLVADEX with or without food. Take your medicine every day. It may be easier to
remember if you take it at the same time each day.
•••• If you forget a dose, take it when you remember, then take the next dose as usual. If it is
almost time for your next dose or you remember at your next dose, do not take extra
tablets to make up the missed dose.
•••• Take NOLVADEX for 5 years, unless your doctor tells you otherwise.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-048
Page 9
What should I avoid while taking NOLVADEX?
•••• Do not become pregnant while taking NOLVADEX or for 2 months after you stop.
NOLVADEX can stop hormonal birth control methods from working. Hormonal
methods include birth control pills, patches, injections, rings and implants. Therefore,
while taking NOLVADEX, use birth control methods that don’t use hormones, such
as condoms, diaphragms with spermicide, or plain IUD’s. If you get pregnant, stop
taking NOLVADEX right away and call your doctor.
•••• Do not breast feed. We do not know if NOLVADEX can pass through your milk and if
it can harm the baby.
What should I do while taking NOLVADEX?
•••• Have regular gynecology check-ups (“female exams”), breast exams and mammograms.
Your doctor will tell you how often. These will check for signs of breast cancer and
cancer of the endometrium (lining of the uterus). Because NOLVADEX does not prevent
all breast cancers, and you may get other types of cancers, you need these exams to find
any cancers as early as possible.
•••• Because NOLVADEX can cause serious side effects, pay close attention to your body.
Signs you should look for are listed in “What are the possible side effects of
NOLVADEX?”
•••• Tell all of the doctors that you see that you are taking NOLVADEX.
•••• Tell your doctor right away if you have any new breast lumps.
General information about the safe and effective use of NOLVADEX
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Your doctor has prescribed NOLVADEX only for you. Do not give it to other people, even if
they have a similar condition, because it may harm them. Do not use it for a condition for which
it was not prescribed.
This Medication Guide is a summary of information about NOLVADEX for women who use
NOLVADEX to lower their high chance of getting breast cancer or who have DCIS. If you want
more information about NOLVADEX, ask your doctor or pharmacist. They can give you
information about NOLVADEX that is written for health professionals. For more information
about NOLVADEX or breast cancer, please visit www.NOLVADEX.com or call 1-800-236-
9933.
Ingredients: tamoxifen citrate, carboxymethylcellulose calcium, magnesium stearate, mannitol
and starch.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-970/S-048
Page 10
*Coumadin is a registered trademark of Bristol-Myers Squibb Pharmaceuticals.
AstraZeneca Pharmaceuticals LP
Wilmington, Delaware 19850-5437
Rev 05-29-03 SIC XXXXX-XX
Printed in USA 2003 AstraZeneca
This Medication Guide has been approved by the US Food and Drug Administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/17970slr048_nolvadex_lbl.pdf', 'application_number': 17970, 'submission_type': 'SUPPL ', 'submission_number': 48}
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PROFESSIONAL INFORMATION BROCHURE
T-10 10/28/98
SIC XXXXX-XX
DESCRIPTION
NOLVADEX_ (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral
administration. NOLVADEX Tablets are available as:
10 mg Tablets. Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10
mg of tamoxifen.
20 mg Tablets. Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20
mg of tamoxifen.
Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and
starch.
Chemically, NOLVADEX is the trans-isomer of a triphenylethylene derivative. The
chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2-hydroxy-
1,2,3- propanetricarboxylate (1:1). The structural and empirical formulas are:
(C32H37NO8)
Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in
water at 37° C is 0.5 mg/mL and in 0.02 N HCl at 37° C, it is 0.2 mg/mL.
NOLVADEX®
(tamoxifen citrate)
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CLINICAL PHARMACOLOGY
NOLVADEX is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in
animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for
binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma
induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-
induced tumors. In this rat model, tamoxifen appears to exert its anti-tumor effects by binding the estrogen
receptors.
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for
estrogen receptor protein.
Tamoxifen is extensively metabolized after oral administration. Studies in women receiving 20 mg
of 14C tamoxifen have shown that approximately 65% of the administered dose is excreted from the body
over a period of 2 weeks with fecal excretion the primary route of elimination. The drug is excreted mainly
as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of
the total fecal radioactivity.
N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of
N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain
primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma.
Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40
ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma
concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The
average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range10 to 20 ng/mL).
Chronic administration of 10 mg tamoxifen given twice daily for three months to patients results in average
steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL
(range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of
tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for three months
are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL), respectively. After
initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4 weeks and steady
state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of
approximately 14 days for this metabolite.
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In a 3-month crossover steady-state bioavailability study with NOLVADEX 10 mg twice a day
versus NOLVADEX 20 mg given once daily, NOLVADEX 20 mg taken once daily had similar
bioavailability to NOLVADEX 10 mg taken twice a day.
•• Clinical Studies - Metastatic Breast Cancer:
Premenopausal Women (NOLVADEX vs. Ablation) - Three prospective, randomized studies
(Ingle, Pritchard, Buchanan) compared NOLVADEX to ovarian ablation (oophorectomy or ovarian
irradiation) in premenopausal women with advanced breast cancer. Although the objective response rate,
time to treatment failure, and survival were similar with both treatments, the limited patient accrual
prevented a demonstration of equivalence. In an overview analysis of survival data from the three studies,
the hazard ratio for death (NOLVADEX/ovarian ablation) was 1.00 with two-sided 95% confidence
intervals of 0.73 to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal
women receiving NOLVADEX, but the data from the randomized studies do not suggest an adverse effect
of this increase. A limited number of premenopausal patients with disease progression during
NOLVADEX therapy responded to subsequent ovarian ablation.
Male Breast Cancer - Published results from 122 patients (119 evaluable) and case reports in 16
patients (13 evaluable) treated with NOLVADEX have shown that NOLVADEX is effective for the
palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients responded to
NOLVADEX which constitutes a 50% objective response rate.
• Clinical Studies - Adjuvant Breast Cancer
Overview - The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted
worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995.
In 1998, 10-year outcome data were reported for 36,689 women in 55 randomized trials of adjuvant
NOLVADEX using doses of 20-40 mg/day for 1-5+ years. Twenty-five percent of patients received one
year or less of trial treatment, 52% received 2 years, and 23% received about 5 years. Forty-eight percent of
tumors were estrogen receptor (ER) positive (> 10 fmol/mg), 21% were ER poor (< 10 fmol/l), and 31%
were ER unknown. Among 29,441 patients with ER positive or unknown breast cancer, 58% were entered
into trials comparing NOLVADEX to no adjuvant therapy and 42% were entered into trials comparing
NOLVADEX in combination with chemotherapy vs. the same chemotherapy alone. Among these patients,
54% had node positive disease and 46% had node negative disease.
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Among women with ER positive or unknown breast cancer and positive nodes who received about 5
years of treatment, overall survival at 10 years was 61.4% for NOLVADEX vs. 50.5% for control (logrank
2p < 0.00001). At ten years, the recurrence rate was 59.7% for NOLVADEX vs. 44.5% for control (logrank
2p < 0.00001). Among women with ER positive or unknown breast cancer and negative nodes who
received about 5 years of treatment, overall survival at 10 years was 78.9% for NOLVADEX vs. 73.3% for
control (logrank 2p < 0.00001). At ten years, the recurrence rate was 79.2% for NOLVADEX vs. 64.3% for
control (logrank 2p < 0.00001).
The effect of the scheduled duration of tamoxifen may be described as follows. In women with ER
positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of NOLVADEX, the
proportional reductions in mortality were 12%, 17% and 26%, respectively (trend significant at 2p <
0.003). The corresponding reductions in breast cancer recurrence were 21%, 29% and 47% (trend
significant at 2p < 0.00001).
Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in
recurrence was 10% (2p=0.007) for all durations taken together, or 9% (2p=0.02) if contralateral breast
cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects of about 5 years
of NOLVADEX on recurrence and mortality were similar regardless of age and concurrent chemotherapy.
There was no indication that doses greater than 20 mg per day were more effective.
Node Positive - Individual Studies - Two studies (Hubay and NSABP B-09) demonstrated an
improved disease-free survival following radical or modified radical mastectomy in postmenopausal women
or women 50 years of age or older with surgically curable breast cancer with positive axillary nodes when
NOLVADEX was added to adjuvant cytotoxic chemotherapy. In the Hubay study, NOLVADEX was added
to "low-dose" CMF (cyclophosphamide, methotrexate and fluorouracil). In the NSABP B-09 study,
NOLVADEX was added to melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).
In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more likely to
benefit. In the NSABP B-09 study in women age 50-59 years, only women with both estrogen and
progesterone receptor levels 10 fmol or greater clearly benefited, while there was a nonstatistically
significant trend toward adverse effect in women with both estrogen and progesterone receptor levels less
than 10 fmol. In women age 60-70 years, there was a trend toward a beneficial effect of NOLVADEX
without any clear relationship to estrogen or progesterone receptor status.
Three prospective studies (ECOG-1178, Toronto, NATO) using NOLVADEX adjuvantly as a single
agent demonstrated an improved disease-free survival following total mastectomy and axillary dissection
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for postmenopausal women with positive axillary nodes compared to placebo/no treatment controls. The
NATO study also demonstrated an overall survival benefit.
Node Negative - Individual Studies - NSABP B-14, a prospective, double-blind, randomized study,
compared NOLVADEX to placebo in women with axillary node-negative, estrogen-receptor positive (>10
fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary
dissection, or segmental resection, axillary dissection, and breast radiation). After five years of treatment,
there was a significant improvement in disease-free survival in women receiving NOLVADEX. This
benefit was apparent both in women under age 50 and in women at or beyond age 50.
One additional randomized study (NATO) demonstrated improved disease-free survival for
NOLVADEX compared to no adjuvant therapy following total mastectomy and axillary dissection in
postmenopausal women with axillary node-negative breast cancer. In this study, the benefits of
NOLVADEX appeared to be independent of estrogen receptor status.
Duration of Therapy - In the EBCTCG 1995 overview, the reduction in recurrence and mortality
was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a
shorter period of therapy.
In the NSABP B-14 trial, in which patients were randomized to NOLVADEX 20 mg/day for 5 years
versus placebo and were disease-free at the end of this 5-year period were offered rerandomization to an
additional five years of NOLVADEX or placebo. With four years of follow-up after this rerandomization,
92% of the women that received five years of NOLVADEX wereare alive and disease-free, compared to
86% of the women scheduled to receive 10 years of NOLVADEX (p=0.003). Overall survivals were 96%
and 94%, respectively (p=0.08). Results of the B-14 study suggest that continuation of therapy beyond five
years does not provide additional benefit.
A Scottish trial of five years of tamoxifen versus indefinite treatment found a disease-free survival of
70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up (HR=1.27,
95% CI 0.87-1.85).
In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of adjuvant
NOLVADEX 40 mg/day for 2 or 5 years, overall survival at ten years was estimated to be 80% in the
patients in the five-year tamoxifen group, compared with 74% among corresponding patients in the two-
year treatment group (p=0.03). Disease-free survival at ten years was 73% in the five-year group and 67%
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in the two-year group (p=0.009). Compared with two years of tamoxifen treatment, five years of treatment
resulted in a slightly greater reduction in the incidence of contralateral breast cancer at ten years, but this
difference was not statistically significant.
Contralateral Breast Cancer - The incidence of contralateral breast cancer is reduced in breast
cancer patients (premenopausal and postmenopausal) receiving NOLVADEX compared to placebo. Data
on contralateral breast cancer are available from 32,422 out of 36,689 patients in the 1995 overview
analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with
NOLVADEX of 1 year or less, 2 years, and about 5 years duration, the proportional reductions in the
incidence rate of contralateral breast cancer among women receiving NOLVADEX were 13% (NS), 26%
(2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer tamoxifen duration (2p =
0.008). The proportional reduction in the incidence of contralateral breast cancer were independent of age
and ER status of the primary tumor. Treatment with about 5 years of NOLVADEX reduced the annual
incidence rate of contralateral breast cancer from 7.6 per 1000 patients in the control group compared with
3.9 per 1000 patients in the tamoxifen group.
In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant NOLVADEX 40 mg/day
for 2-5 years, the incidence of second primary breast tumors was reduced 40% (p<0.008) on tamoxifen
compared to control. In the NSABP B-14 trial in which patients were randomized to NOLVADEX 20
mg/day for 5 years versus placebo, the incidence of second primary breast cancers was also significantly
reduced (p<0.01). In NSABP B-14, the annual rate of contralateral breast cancer was 8.0 per 1000 patients
in the placebo group compared with 5.0 per 1000 patients in the tamoxifen group, at 10 years after first
randomization.
Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women: The Breast
Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo controlled trial with
a primary objective to determine whether five years of NOLVADEX therapy (20 mg/day)would reduce the
incidence of invasive breast cancer in women at high risk for the disease. (See INDICATIONS AND
USAGE). Secondary objectives included an evaluation of the incidence of ischemic heart disease; the
effects on the incidence of bone fractures; and other events that might be associated with the use of
NOLVADEX, including: endometrial cancer, pulmonary embolus, deep vein thrombosis, stroke, and
cataract formation and surgery (See WARNINGS).
The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60
years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age;
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number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of
atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5-year predicted risk of
breast cancer of > 1.67% was required for entry into the trial.
In this trial, 13,388 women of at least 35 years of age were randomized to receive either
NOLVADEX or placebo for five years. The median duration of treatment was 3.5 years. As of January 31,
1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to
placebo (1782) and 24% of women randomized to NOLVADEX (1596) completed 5 years of therapy. The
demographic characteristics of women on the trial with follow-up data are shown in Table 1.
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(tamoxifen citrate)
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Table 1. Demographic Characteristics of Women in the
NSABP P-1 Trial
Characteristic
Placebo
Tamoxifen
#
%
#
%
Age (yrs.)
35-39
184
3
158
2
40-49
2,394
36
2,411
37
50-59
2,011
31
2,019
31
60-69
1,588
24
1,563
24
≥70
393
6
393
6
Age at first live birth(yrs.)
Nulliparous
1,202
18
1,205
18
12-19
915
14
946
15
20-24
2,448
37
2,449
37
25-29
1,399
21
1,367
21
≥30
606
9
577
9
Race
White
6,333
96
6,323
96
Black
109
2
103
2
Other
128
2
118
2
Age at menarche
≥14
1,243
19
1,170
18
12-13
3,610
55
3,610
55
≤11
1,717
26
1,764
27
# of first degree relatives with breast cancer
0
1,584
24
1,525
23
1
3,714
57
3,744
57
2+
1,272
19
1,275
20
Prior Hysterectomy
No
4173
63.5
4018
62.4
Yes
2397
36.5
2464
37.7
# of previous breast biopsies
0
2,935
45
2,923
45
1
1,833
28
1,850
28
≥ 2
1,802
27
1,771
27
History of atypical hyperplasia in the breast
No
5,958
91
5,969
91
Yes
612
9
575
9
History of LCIS at entry
No
6,165
94
6,135
94
Yes
405
6
409
6
5-year predicted breast cancer risk (%)
≤2.00
1,646
25
1,626
25
2.01-3.00
2,028
31
2,057
31
3.01-5.00
1,787
27
1,707
26
≥5.01
1,109
17
1,162
18
Total
6,570 100.0
6,544
100.0
Results are shown in Table 2. After a median follow-up of 4.2 years, the incidence of invasive
breast cancer was reduced by 44% among women assigned to NOLVADEX (86 cases-NOLVADEX, 156
cases-placebo; p<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A reduction in the incidence of
breast cancer was seen in each prospectively specified age group (< 49, 50-59, > 60), in women with or
without LCIS, and in each of the absolute risk levels specified in Table 2. A non-significant decrease in the
incidence of ductal carcinoma in situ (DCIS) was seen (23-NOLVADEX, 35-placebo; RR=0.66; 95% CI:
0.39-1.11).
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There was no statistically significant difference in the number of myocardial infarctions, severe
angina, or acute ischemic cardiac events between the two groups (61-NOLVADEX, 59-placebo; RR=1.04,
95% CI 0.73-1.49).
No overall difference in mortality (53 deaths in NOLVADEX group versus 65 deaths in placebo
group) was present. No difference in breast cancer-related mortality was observed (4 deaths in
NOLVADEX group versus 5 deaths in placebo group).
Although there was a non-significant reduction in the number of hip fractures (9 on NOLVADEX,
20 on placebo) in the NOLVADEX group, the number of wrist fractures was similar in the two treatment
groups (69 on NOLVADEX, 74 on placebo). No information regarding bone mineral density or other
markers of osteoporosis is available.
The risks of NOLVADEX therapy include endometrial cancer, DVT, PE, stroke, cataract formation
and cataract surgery (See Table 2). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed
in the NOLVADEX group versus 14 in the placebo group (RR=2.48, 95% CI 1.27-4.92). Deep vein
thrombosis was observed in 30 women receiving NOLVADEX versus 19 in women receiving placebo
(RR=1.59, 95% CI 0.86-2.98). Eighteen cases of pulmonary embolism were observed in the NOLVADEX
group versus 6 in the placebo group (RR=3.01, 95% CI 1.15-9.27). There were 34 strokes on the
NOLVADEX arm and 24 on the placebo arm (RR 1.42; 95% CI 0.82-2.51). Cataract formation in women
without cataracts at baseline was observed in 540 women taking NOLVADEX versus 483 women receiving
placebo (RR=1.13, 95% CI 1.00-1.28). Cataract surgery (with or without cataracts at baseline) was
performed in 201 women taking NOLVADEX versus 129 women receiving placebo ( RR=1.51, 95% CI
1.21-1.89) (See WARNINGS).
Table 2 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following
results are presented: the number of events and rate per 1000 women per year for the placebo and
NOLVADEX groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between
NOLVADEX and placebo. Relative risks less than 1.0 indicate a benefit of NOLVADEX therapy. The
limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of
NOLVADEX therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit
exists. For most participants, multiple risk factors would have been required for eligibility. This table
considers risk factors individually, regardless of other co-existing risk factors, for women who developed
breast cancer. The five-year predicted absolute breast cancer risk accounts for multiple risk factors in an
individual and should provide the best estimate of individual benefit (See INDICATIONS AND USAGE)
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Table 2: Major Outcomes of the NSABP P-1 Trial
# OF EVENTS
RATE/1000 WOMEN/YEAR
95% CI
TYPE OF EVENT
PLACEBO NOLVADEX PLACEBO NOLVADEX RR LIMITS
Invasive Breast Cancer
156
86
6.49
3.58
0.56 0.43-0.72
Age <49
59
38
6.34
4.11
0.65 0.43-0.98
Age 50-59
46
25
6.31
3.53
0.56 0.35-0.91
Age ≥60
51
23
7.17
3.22
0.45 0.27-0.74
Risk Factors for Breast Cancer
History, LCIS
No
140
78
6.23
3.51
0.56 0.43-0.74
Yes
16
8
12.73
6.33
0.50 0.21-1.17
History, Atypical Hyperplasia
No
138
84
6.37
3.89
0.61 0.47-0.80
Yes
18
2
8.69
1.05
0.12 0.03-0.52
No. First Degree Relatives
0
32
17
5.97
3.26
0.55 0.30-0.98
1
80
45
5.81
3.31
0.57 0.40-0.82
2
35
18
8.92
4.67
0.52 0.30-0.92
≥3
9
6
13.33
7.58
0.57 0.20-1.59
5-Year Predicted Breast Cancer Risk
(as calculated by the Gail Model)
<2.00%
31
13
5.36
2.26
0.42 0.22-0.81
2.01-3.00%
39
28
5.25
3.83
0.73 0.45-1.18
3.01-5.00%
36
26
5.37
4.06
0.76 0.46-1.26
≥5.00%
50
19
13.15
4.71
0.36 0.21-0.61
DCIS
35
23
1.47
0.97
0.66 0.39-1.11
Fractures (protocol-specified sites)
921
761
3.87
3.20
0.61 0.83-1.12
Hip
20
92
0.84
0.38
0.45 0.18-1.04
Wrist2
74
69
3.11
2.91
0.93
0.67-1.29
Total Ischemic Events
59
61
2.47
2.57
1.04 0.71-1.51
Myocardial Infarction
27
27
1.13
1.13
1.00 0.57-1.78
Fatal
8
7
0.33
0.29
0.88 0.27-2.77
Nonfatal
19
20
0.79
0.84
1.06 0.54-2.09
Angina33
12
12
0.50
0.50
1.00 0.41-2.44
Acute Ischemic Syndrome44
20
22
0.84
0.92
1.11 0.58-2.13
Invasive Endometrial Cancer (among
women without a hysterectomy)
14
33
0.92
2.29
2.48 1.27-4.92
Stroke55
24
34
1.00
1.43
1.42 0.82-2.51
Transient Ischemic Attack
21
18
0.88
0.75
0.86
0.43-1.70
Pulmonary Emboli6
6
18
0.25
0.75
3.01
1.15-9.27
Deep-Vein Thrombosis7
19
30
0.79
1.26
1.59
0.86-2.98
Cataracts Developing on Study8
483
540
22.51
25.41
1.13
1.00-1.28
Underwent Cataract Surgery8
63
101
31.43
46.62
1.48
1.08-2.03
Underwent Cataract Surgery9
129
201
37.58
56.81
1.51
1.21-1.89
1Two women had hip and wrist fractures
2 Includes Colles' and other lower radius fractures
3Requiring angioplasty or CABG
4New Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring hospitalization without surgery
5Seven cases were fatal; three in the placebo group and four in the NOLVADEX group
6Three cases in the NOLVADEX group were fatal
7All but three cases in each group required hospitalization
8Based on women without cataracts at baseline (6230 Placebo, 6199 NOLVADEX)
9All women. (6707-Placebo, 6681-NOLVADEX)
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Table 3 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes tumor
size, nodal status, ER status. NOLVADEX decreased the incidence of small estrogen receptor positive
tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors.
Table 3: Characteristics of Breast Cancer in NSABP P-1 Trial
Staging Parameter
Placebo
Tamoxifen
Total
N=156154
N=8685
N=242239
Tumor size:
T1
117
60
177
T2
28
20
48
T3
7
3
10
T4
1
2
3
Unknown
3
10
4
Nodal status:
Negative
103
56
159
1-3 positive nodes
29
14
43
≥ 4 positive nodes
10
12
22
Unknown
14
4
18
Stage:
I
88
47
135
II: node negative
15
9
24
II: node positive
33
22
55
III
6
4
10
IV
21
1
3
Unknown
12
3
15
Estrogen receptor:
Positive
115
38
153
Negative
27
36
63
Unknown
14
12
26
1 1 participant presented with a suspicious bone scan but did not have documented metastases. She subsequently died of metastatic breast cancer..
Interim results from two trials in addition to the NSABP P-1 trial examining the effects of tamoxifen
in reducing breast cancer incidence have been reported.
The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35 and
70, who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or matching placebo
for 5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Women
without any specific risk factors for breast cancer were to be entered. Between 1992 and 1997, 5408
women were randomized. Hormone Replacement Therapy (HRT) was used in 14% of participants. The
trial closed in 1997 due to the large number of dropouts during the first year of treatment (26%). After 46
months of follow-up there were 22 breast cancers in women on placebo and 19 in women on tamoxifen.
Although no decrease in breast cancer incidence was observed, there was a trend for a reduction in breast
cancer among women receiving protocol therapy for at least one year (19-placebo, 11- tamoxifen). The
small numbers of participants along with the low level of risk in this otherwise healthy group precluded an
adequate assessment of the effect of tamoxifen in reducing the incidence of breast cancer.
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The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT
was, begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial was
subsequently extended to a pilot trial to accrue additional participants to further assess the safety of
tamoxifen. 2471 women were entered between 1986 and 1996; they were selected on the basis of a family
history of breast cancer. HRT was used in 40% of participants. In this trial, with a 70-month median
follow-up, 34 and 36 breast cancers (8 noninvasive, 4 on each arm) were observed among women on
tamoxifen and placebo, respectively. Patients in this trial were younger than those in the NSABP P-1 trial
and may have been more likely to develop ER(-) tumors, which are unlikely to be reduced in number by
tamoxifen therapy. Although women were selected on the basis of family history and were thought to have
a high risk of breast cancer, few events occurred, reducing the statistical power of the study. These factors
are potential reasons why the RMT may not have provided an adequate assessment of the effectiveness of
tamoxifen in reducing the incidence of breast cancer.
In these trials, an increased number of cases of deep vein thrombosis, pulmonary embolus, stroke,
and endometrial cancer were observed on the tamoxifen arm compared to the placebo arm. The frequency
of events was consistent with the safety data observed in the NSABP P-1 trial.
INDICATIONS AND USAGE
Metastatic Breast Cancer: NOLVADEX is effective in the treatment of metastatic breast cancer
in women and men. In premenopausal women with metastatic breast cancer, NOLVADEX is an
alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose
tumors are estrogen receptor positive are more likely to benefit from NOLVADEX therapy.
Adjuvant Treatment of Breast Cancer: NOLVADEX is indicated for the treatment of node-
positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy,
axillary dissection, and breast irradiation. In some NOLVADEX adjuvant studies, most of the benefit to
date has been in the subgroup with 4 or more positive axillary nodes.
NOLVADEX is indicated for the treatment of axillary node-negative breast cancer in women
following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. Data are
insufficient to predict which women are most likely to benefit and to determine if NOLVADEX provides
any benefit in women with tumors less than 1 cm.
NOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant
NOLVADEX therapy for breast cancer.
NOLVADEX®
(tamoxifen citrate)
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Current data from clinical trials support five years of adjuvant NOLVADEX therapy for patients
with breast cancer.
The estrogen and progesterone receptor values may help to predict whether adjuvant NOLVADEX
therapy is likely to be beneficial.
Reduction in Breast Cancer Incidence in High Risk Women: NOLVADEX is indicated to reduce
the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of
5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants
received drug for 5 years. The longer term effects are not known. In this study, there was no impact of
tamoxifen on overall or breast cancer-related mortality.
NOLVADEX is indicated only for high-risk women. “High risk” is defined as women at least 35
years of age with a 5-year predicted risk of breast cancer > 1.67%, as calculated by the Gail model.
Examples of combinations of factors predicting a 5-year risk > 1.67% are:
Age 35 or older and any of the following combination of factors:
•
One first degree relative with a history of breast cancer, two or more benign biopsies, and a history of a
breast biopsy showing atypical hyperplasia; or
•
At least two first degree relatives with a history of breast cancer, and a personal history of at least one
breast biopsy; or
•
LCIS
Age 40 or older and any of the following combination of factors:
•
One first degree relative with a history of breast cancer, two or more benign biopsies, age at first live
birth 25 or older, and age at menarche 11 or younger; or
•
At least two first degree relatives with a history of breast cancer, and age at first live birth 19 or
younger; or
•
One first degree relative with a history of breast cancer, and a personal history of a breast biopsy
showing atypical hyperplasia.
Age 45 or older and any of the following combination of factors:
•
At least two first degree relatives with history of breast cancer and age at first live birth 24 or younger;
or
NOLVADEX®
(tamoxifen citrate)
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•
One first degree relative with a history of breast cancer with a personal history of a benign breast
biopsy, age at menarche 11 or less and age at first live birth 20 or more.
Age 50 or older and any of the following combination of factors:
•
At least two first degree relatives with a history of breast cancer; or
•
History of one breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age
at menarche 11 or less; or
•
History of at least two breast biopsies with a history of atypical hyperplasia, and age at first live birth
30 or more.
Age 55 and any of the following combination of factors:
•
One first degree relative with a history of breast cancer with a personal history of a benign breast
biopsy, and age at menarche 11 or less; or
•
History of at least two breast biopsies with a history of atypical hyperplasia, and age at first live birth
20 or older.
Age 60 or older and:
•
5 year predicted risk of breast cancer 1.67%, as calculated by the Gail Model.
For women whose risk factors are not described in the above examples, the Gail Model is necessary
to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment
Tool by dialing 1-800-456-3669 (Ext. 3838).
There are no data available regarding the effect of NOLVADEX on breast cancer incidence in
women with inherited mutations (BRCA1, BRCA2).
After an assessment of the risk of developing breast cancer, the decision regarding therapy with
NOLVADEX for the reduction in breast cancer incidence should be based upon an individual assessment of
the benefits and risks of NOLVADEX therapy. In the NSABP P-1 trial, NOLVADEX treatment lowered
the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast
cancer risk (See Table 2 in CLINICAL PHARMACOLOGY).
NOLVADEX®
(tamoxifen citrate)
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CONTRAINDICATIONS
NOLVADEX is contraindicated in patients with known hypersensitivity to the drug.
Reduction in Breast Cancer Incidence In High Risk Women: NOLVADEX is contraindicated in
women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep
vein thrombosis or pulmonary embolus.
WARNINGS
Effects in Metastatic Breast Cancer Patients: As with other additive hormonal therapy (estrogens
and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases
within a few weeks of starting treatment with NOLVADEX. If hypercalcemia does occur, appropriate
measures should be taken and, if severe, NOLVADEX should be discontinued.
Effects on the Uterus-Endometrial Cancer: As with other additive hormonal therapy (estrogens),
an increased incidence of endometrial cancer has been reported in association with NOLVADEX treatment.
The underlying mechanism is unknown, but may be related to the estrogen-like effect of NOLVADEX.
Any patients receiving or having previously received NOLVADEX, who report abnormal vaginal bleeding
should be promptly evaluated. Patients receiving or having previously received NOLVADEX should have
routine gynecological care and they should promptly inform their physician if they experience any
abnormal gynecological symptoms, e.g., menstrual irregularities, abnormal vaginal bleeding, changes in
vaginal discharge, or pelvic pain or pressure.
In a large randomized trial in Sweden of adjuvant NOLVADEX 40 mg/day for 2-5 years, an
increased incidence of uterine cancer was noted. Twenty three of 1,372 patients randomized to receive
NOLVADEX versus 4 of 1,357 patients randomized to the observation group developed cancer of the
uterus [RR = 5.6 (1.9-16.2), p<.001]. One of the patients with cancer of the uterus who was randomized to
receive NOLVADEX never took the drug. After approximately 6.8 years of follow-up in the NSABP B-14
trial, 15 of 1,419 women randomized to receive NOLVADEX 20 mg/day for 5 years developed uterine
cancer and 2 of the 1,424 women randomized to receive placebo, who subsequently were treated with
NOLVADEX, also developed uterine cancer. Most of the uterine cancers were diagnosed at an early stage,
but
deaths
from
uterine
cancer
have
been
reported.
NOLVADEX®
(tamoxifen citrate)
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In the NSABP P-1 trial, among participants randomized to NOLVADEX there was a statistically
significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer,
compared to 14 cases among participants randomized to placebo (RR 2.48, 95% CI 1.27-4.92). This
increase was primarily observed among women at least 50 years of age at the time of randomization (26
cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR
4.50, 95% CI 1.78-13.16). Among women ≤ 49 years of age at the time of randomization there were 7
cases of invasive endometrial cancer, compared to 8 cases among participants randomized to placebo (RR
0.94, 95% CI 0.28-2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial
cancer among participants < 49 randomized to NOLVADEX compared to 2 among participants
randomized to placebo (RR 2.21, 95% CI 0.4-12.0). For women > 50 at the time of diagnosis, there were
29 cases among participants randomized to NOLVADEX compared to 12 among women on placebo (RR
2.5, 95% CI 1.3-4.9). The risk ratios were similar in the two groups, although fewer events occurred in
younger women. Most (29 of 33 cases in the NOLVADEX group) endometrial cancers were diagnosed in
symptomatic women; although 5 of 33 cases in the NOLVADEX group occurred in asymptomatic women.
Among women receiving NOLVADEX the events appeared between 1 and 61 months (average=32 months)
from the start of treatment.
Among participants receiving NOLVADEX, there were 33 cases of FIGO stage I [20 IA, 12 IB, and
1 IC] endometrial cancer. Among participants receiving placebo, there were 13 FIGO stage I cases [8 IA
and 5 IB]. There was a single FIGO Stage IV endometrial cancer in a participant receiving placebo. (See
Table 2 in CLINICAL PHARMACOLOGY). The distribution of FIGO stage was similar between
participants receiving NOLVADEX and placebo. Five women receiving NOLVADEX and 1 receiving
placebo with FIGO Stage IB disease received postoperative radiation therapy in addition to surgery.
Endometrial sampling did not alter the endometrial cancer detection rate compared to women who
did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women with an
intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women
taking NOLVADEX to reduce the incidence of breast cancer would be beneficial.
Non-Malignant Effects on the Uterus: An increased incidence of endometrial changes including
hyperplasia and polyps have been reported in association with NOLVADEX treatment. The incidence and
pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of
NOLVADEX.
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(tamoxifen citrate)
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There have been a few reports of endometriosis and uterine fibroids in women receiving
NOLVADEX. The underlying mechanism may be due to the partial estrogenic effect of NOLVADEX.
Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast
cancer who have been treated with NOLVADEX.
Thromboembolic Effects of NOLVADEX: For treatment of breast cancer, the risks and benefits of
NOLVADEX should be carefully considered in women with a history of thromboembolic events.
Data from the P-1 trial show that participants receiving NOLVADEX without a history of
pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-Nolvadex, 6-
placebo, RR=3.01, 95% CI: 1.15- 9.27). Three of the pulmonary emboli, all in the NOLVADEX arm, were
fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age
at randomization. Among women receiving NOLVADEX, the events appeared between 2 and 60 months
(average=27 months) from the start of treatment.
In this same population, a non-statistically significant increase in deep vein thrombosis (DVT) was
seen in the NOLVADEX group (30-NOLVADEX, 19-placebo; RR=1.59, 95% CI: 0.86-2.98). The same
increase in relative risk was seen in women < 49 and in women > 50, although fewer events occurred in
younger women. Women with thromboembolic events were at risk for a second related event (7 out of 25
women on placebo, 5 out of 48 women on NOLVADEX) and were at risk for complications of the event
and its treatment (0/25 on placebo, 4/48 on NOLVADEX). Among women receiving NOLVADEX, deep
vein thrombosis events occurred between 2 and 57 months (average=19 months) from the start of treatment.
There was a non-statistically significant increase in stroke among patients randomized to
NOLVADEX (24- Placebo; 34-NOLVADEX; RR 1.42; 95% CI 0.82-2.51). Six of the 24 strokes in the
placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the NOLVADEX group
were categorized as hemorrhagic. Seventeen of the 34 stokes in the NOLVADEX group were considered
occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm
were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the placebo
group and 4 strokes in the NOLVADEX group were fatal. Eighty-eight percent of the strokes occurred in
women at least 50 years of age at the time of randomization. Among women receiving NOLVADEX, the
events occurred between 1 and 63 months (average=30 months) from the start of treatment.
Effects on the liver: Liver cancer: In the Swedish trial using adjuvant NOLVADEX 40 mg/day
for 2-5 years, 3 cases of liver cancer have been reported in the NOLVADEX-treated group versus 1 case in
NOLVADEX®
(tamoxifen citrate)
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the observation group (See PRECAUTIONS-Carcinogenesis). In other clinical trials evaluating
NOLVADEX, no cases of liver cancer have been reported to date.
No cases of liver cancer were reported in NSABP P-1 with a median follow-up of 4.2 years.
Effects on the liver: Non-malignant effects: NOLVADEX has been associated with changes in
liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty
liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most
reported cases the relationship to NOLVADEX is uncertain. However, some positive rechallenges and
dechallenges have been reported.
In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin, alkaline
phosphatase) were observed (10 on placebo and 6 on NOLVADEX). Serum lipids were not systematically
collected.
Other cancers: A number of second primary tumors, occurring at sites other than the endometrium,
have been reported following the treatment of breast cancer with NOLVADEX in clinical trials. Data from
the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving
NOLVADEX. Whether an increased risk for other (non-uterine) cancers is associated with NOLVADEX is
still uncertain and continues to be evaluated.
Effects on the Eye: Ocular disturbances, including corneal changes, cataracts, the need for cataract
surgery, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported
in patients receiving NOLVADEX.
In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among
those women without cataracts at baseline (540 NOLVADEX; 483 placebo; RR=1.13, 95% CI 1.00-1.28)
was observed. Among these same women, NOLVADEX was associated with an increased risk of having
cataract surgery (101 NOLVADEX; 63 placebo; RR=1.62, 95% CI 1.17-2.25). (See Table 2 in
CLINICAL PHARMACOLOGY) Among all women on the trial (with or without cataracts at baseline),
NOLVADEX was associated with an increased risk of having cataract surgery (201 NOLVADEX; 129
placebo; RR=1.51, 95% CI 1.21-1.89). Eye examinations were not required during the study. No other
conclusions regarding non-cataract ophthalmic events can be made.
NOLVADEX®
(tamoxifen citrate)
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Pregnancy Category D: NOLVADEX may cause fetal harm when administered to a pregnant
woman. Women should be advised not to become pregnant while taking NOLVADEX and should use
barrier or nonhormonal contraceptive measures if sexually active. Effects on reproductive functions are
expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels equal
to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found
reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below
those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or
retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to
historical controls. Several pregnant marmosets were dosed during organogenesis or in the last half of
pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in
some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations.
In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.3 to 2.4-fold the
human maximum recommended dose on a mg/m2 basis) caused changes in both sexes that are similar to
those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these
changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young
women who were exposed to diethylstilbestrol in utero and who have a 1 in 1000 risk of developing clear-
cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to
cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in young women. However,
only a small number of young women have been exposed to tamoxifen in utero, and a smaller number have
been followed long enough (to age 15-20) to determine whether vaginal or cervical neoplasia could occur as
a result of this exposure.
There are no adequate and well controlled trials of tamoxifen in pregnant women. There have been
a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in
pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this
drug, or within approximately two months after discontinuing therapy, the patient should be apprised of the
potential risks to the fetus including the potential long term risk of a DES-like syndrome.
Reduction in Breast Cancer Incidence In High Risk Women - Pregnancy Category D: For
sexually active women of child-bearing potential, NOLVADEX therapy should be initiated during
menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation
of therapy is sufficient. (See PRECAUTIONS-Information for Patients - Reduction in Breast Cancer
Incidence in High Risk Women).
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(tamoxifen citrate)
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PRECAUTIONS
General: Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have
been occasionally reported in patients taking NOLVADEX for breast cancer. In patients with significant
thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to
NOLVADEX therapy. Leukopenia has been observed, sometimes in association with anemia and/or
thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving
NOLVADEX; this can sometimes be severe.
In the NSABP P-1 trial, 6 women on NOLVADEX and 2 on placebo experienced grade 3-4 drops in
platelet counts (≤50, 0003/mm).
Information for Patients:
Reduction in Breast Cancer Incidence In High Risk Women: Women who are at high risk for
breast cancer can consider taking NOLVADEX therapy to reduce the incidence of breast cancer. Whether
the benefits of treatment are considered to outweigh the risks depends on a woman's personal health history
and on how she weighs the benefits and risks. NOLVADEX therapy to reduce the incidence of breast
cancer may therefore not be appropriate for all women at high risk for breast cancer. Women who are
considering NOLVADEX therapy should consult their health care professional for an assessment of the
potential benefits and risks prior to starting therapy for reduction in breast cancer incidence. (See Table 2
in the CLINICAL PHARMACOLOGY) Women should understand that NOLVADEX reduces the
incidence of breast cancer, but may not eliminate risk. NOLVADEX decreased the incidence of small
estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or
larger tumors. In women with breast cancer who are at high risk of developing a second breast cancer,
treatment with about 5 years of NOLVADEX reduced the annual incidence rate of a second breast cancer
by approximately 50%.
Women who are pregnant or who plan to become pregnant should not take NOLVADEX to reduce
her risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women
taking NOLVADEX if they are sexually active. For sexually active women of child-bearing potential,
NOLVADEX therapy should be initiated during menstruation. In women with menstrual irregularity, a
negative B-HCG immediately prior to the initiation of therapy is sufficient.(See WARNINGS-Pregnancy
Category D.)
Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no
difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies had
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(tamoxifen citrate)
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trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled women at
a lower risk for breast cancer than those in P-1.
Monitoring During NOLVADEX Therapy: Women taking or having previously taken
NOLVADEX should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding,
gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure),
symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women
should inform all care providers, regardless of the reason for evaluation, that they take NOLVADEX.
Women taking NOLVADEX to reduce the incidence of breast cancer should have a breast
examination, a mammogram, and a gynecologic examination prior to the initiation of therapy. These
studies should be repeated at regular intervals while on therapy, in keeping with good medical practice.
Women taking NOLVADEX as adjuvant breast cancer therapy should follow the same monitoring
procedures as for women taking NOLVADEX for the reduction in the incidence of breast cancer. Women
taking NOLVADEX as treatment for metastatic breast cancer should review this monitoring plan with their
care provider and select the appropriate modalities and schedule of evaluation.
Laboratory Tests: Periodic complete blood counts, including platelet counts, and periodic liver
function tests should be obtained.
Drug Interactions: When NOLVADEX is used in combination with coumarin-type anticoagulants,
a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful
monitoring of the patient's prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulats for any reason were
ineligible for participation in the trial. (See CONTRAINDICATIONS).
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in
combination with NOLVADEX.
Tamoxifen, N-desmethyl tamoxifen and 4-hydroxytamoxifen have been found to be potent inhibitors
of hepatic cytochrome p-450 mixed function oxidases. The effect of tamoxifen on metabolism and
excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed
function oxidases for activation, is not known.
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One patient receiving NOLVADEX with concomitant phenobarbital exhibited a steady state serum
level of tamoxifen lower than that observed for other patients (i.e., 26 ng/mL vs. mean value of 122
ng/mL). However, the clinical significance of this finding is not known.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl
tamoxifen.
Drug/Laboratory Testing Interactions: During postmarketing surveillance, T4 elevations were
reported for a few postmenopausal patients which may be explained by increases in thyroid-binding
globulin. These elevations were not accompanied by clinical hyperthyroidism.
Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on
Pap smears have been infrequently seen in postmenopausal patients given NOLVADEX.
In the postmarketing experience with NOLVADEX, infrequent cases of hyperlipidemias have been
reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with pre-
existing hyperlipidemias.
Carcinogenesis: A conventional carcinogenesis study in rats (doses of 5, 20, and 35 mg/kg/day for
up to 2 years) revealed hepatocellular carcinoma at all doses, and the incidence of these tumors was
significantly greater among rats given 20 or 35 mg/kg/day (69%) than those given 5 mg/kg/day (14%).
The incidence of these tumors in rats given 5 mg/kg/day (29.5 mg/m2) was significantly greater than in
controls.
In addition, preliminary data from 2 independent reports of 6-month studies in rats reveal liver
tumors which in one study are classified as malignant. (See WARNINGS)
Endocrine changes in immature and mature mice were investigated in a 13-month study. Granulosa
cell ovarian tumors and interstitial cell testicular tumors were found in mice receiving NOLVADEX, but
not in the controls.
Mutagenesis: Although no genotoxic potential was found in a conventional battery of in vivo and
in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems present, increased levels
of DNA adducts have been found in the livers of rats exposed to tamoxifen. Tamoxifen also has been found
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to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on
these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells.
Impairment of Fertility: Fertility in female rats was decreased following administration of 0.04
mg/kg for two weeks prior to mating through day 7 of pregnancy. There was a decreased number of
implantations, and all fetuses were found dead.
Following administration to rats of 0.16 mg/kg from days 7-17 of pregnancy, there were increased
numbers of fetal deaths. Administration of 0.125 mg/kg to rabbits during days 6-18 of pregnancy resulted
in abortion or premature delivery. Fetal deaths occurred at higher doses. There were no teratogenic
changes in either rat or rabbit segment II studies. Several pregnant marmosets were dosed with 10
mg/kg/day either during organogenesis or in the last half of pregnancy. No deformations were seen, and
although the dose was high enough to terminate pregnancy in some animals, those that did maintain
pregnancy showed no evidence of teratogenic malformations. Rats given 0.16 mg/kg from day 17 of
pregnancy to 1 day before weaning demonstrated increased numbers of dead pups at parturition. It was
reported that some rat pups showed slower learning behavior, but this did not achieve statistical
significance in one study, and in another study where significance was reported, this was obtained by
comparing dosed animals with controls of another study.
The recommended daily human dose of 20-40 mg corresponds to 0.4-0.8 mg/kg for an average 50 kg
woman.
Pregnancy Category D: See WARNINGS.
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Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing
infants from NOLVADEX, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use: The safety and efficacy of NOLVADEX in pediatric patients have not been
established.
Geriatric Use: In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%.
Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer
incidence was seen among participants in each of the subsets; A total of 28 and 10 invasive breast cancers
were seen among participants 65 and older in the placebo and NOLVADEX groups, respectively. Across
all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50
years of age. No overall differences in tolerability were observed between older and younger patients. (See
CLINICAL PHARMACOLOGY - Clinical Studies - Reduction in Breast Cancer Incidence in High
Risk Women section).
ADVERSE REACTIONS
Adverse reactions to NOLVADEX are relatively mild and rarely severe enough to require
discontinuation of treatment in breast cancer patients.
Continued clinical studies have resulted in further information which better indicates the incidence
of adverse reactions with NOLVADEX as compared to placebo.
Metastatic Breast Cancer: Increased bone and tumor pain and, also, local disease flare have
occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain
may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of
preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or
the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after
starting NOLVADEX and generally subside rapidly.
In patients treated with NOLVADEX for metastatic breast cancer, the most frequent adverse
reaction to NOLVADEX is hot flashes.
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Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste
for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/or partial
hair loss, and vaginal dryness.
Premenopausal Women: The following table summarizes the incidence of adverse reactions
reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared
NOLVADEX therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.
OVARIAN
NOLVADEX
ABLATION
All Effects
All Effects
% of Women
% of Women
________________________________________________________________
Adverse Reactions*
n = 104
n = 100
_______________________%_____________ %_______
Flush
33
46
Amenorrhea
16
69
Altered Menses
13
5
Oligomenorrhea
9
1
Bone Pain
6
6
Menstrual Disorder
6
4
Nausea
5
4
Cough/Coughing
4
1
Edema
4
1
Fatigue
4
1
Musculoskeletal Pain
3
0
Pain
3
4
Ovarian Cyst(s)
3
2
Depression
2
2
Abdominal Cramps
1
2
Anorexia
1
2
________________________________________________________________
*Some women had more than one adverse reaction.
Male Breast Cancer: NOLVADEX is well tolerated in males with breast cancer. Reports from
the literature and case reports suggest that the safety profile of NOLVADEX in males is similar to that
seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in
male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen
levels were elevated. No significant clinical changes were reported.
Adjuvant Breast Cancer: In the NSABP B-14 study, women with axillary node-negative breast
cancer were randomized to 5 years of NOLVADEX 20 mg/day or placebo following primary surgery. The
reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse
NOLVADEX®
(tamoxifen citrate)
Page 26
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T-10 10-28 one column
events more common on NOLVADEX than on placebo. The incidence of hot flashes (64% v 48%),
vaginal discharge (30% v 15%), and irregular menses (25% v 19%) were higher with NOLVADEX
compared with placebo. All other adverse effects occurred with similar frequency in the two treatment
groups, with the exception of thrombotic events, a higher incidence was seen in NOLVADEX-treated
patients (through 5 years, 1.7% versus 0.4%). Two of the patients treated with NOLVADEX who had
thrombotic events died.
NSABP B-14 Study
_________________________________________________________
% of Women
Adverse Effect
NOLVADEX
Placebo
(n=1422)
(n=1437)
_________________________________________________________
Hot Flashes
64
48
Fluid Retention
32
30
Vaginal Discharge
30
15
Nausea
26
24
Irregular Menses
25
19
Weight Loss (>5%)
23
18
Skin Changes
19
15
Increased SGOT
5
3
Increased Bilirubin
2
1
Increased Creatinine
2
1
Thrombocytopenia*
2
1
Thrombotic Events
Deep Vein Thrombosis
0.8
0.2
Pulmonary Embolism
0.5
0.2
Superficial Phlebitis
0.4
0.0
_________________________________________________________
*Defined as a platelet count of <100,000/mm3
In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, NOLVADEX or
placebo was administered for 2 years to women following mastectomy. When compared to placebo,
NOLVADEX showed a significantly higher incidence of hot flashes (19% versus 8% for placebo). The
incidence of all other adverse reactions was similar in the 2 treatment groups with the exception of
thrombocytopenia where the incidence for NOLVADEX was 10% versus 3% for placebo, an observation of
borderline statistical significance.
In other adjuvant studies, Toronto and NOLVADEX Adjuvant Trial Organization (NATO), women
received either NOLVADEX or no therapy. In the Toronto study, hot flashes were observed in 29% of
patients, for NOLVADEX versus 1% in the untreated group. In the NATO trial, hot flashes and vaginal
NOLVADEX®
(tamoxifen citrate)
Page 27
______________________________________________________________________________________
T-10 10-28 one column
bleeding were reported in 2.8%, and 2.0% of women, respectively, for NOLVADEX versus 0.2% for each
in the untreated group.
Reduction in Breast Cancer Incidence In High Risk Women: In the NSABP P-1 Trial, there was
an increase in five serious adverse effects in the NOLVADEX group: endometrial cancer (33 cases in the
NOLVADEX group versus 14 in the placebo group); pulmonary embolism (18 cases in the NOLVADEX
group versus 6 in the placebo group); deep vein thrombosis (30 cases in the NOLVADEX group versus 19
in the placebo group); stroke (34 cases in the NOLVADEX group versus 24 in the placebo group); cataract
formation (540 cases in the NOLVADEX group versus 483 in the placebo group) and cataract surgery (101
cases in the NOLVADEX group versus 63 in the placebo group). (See WARNINGS and Table 2 in
CLINICAL PHARMACOLOGY)
The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only
adverse events more common on NOLVADEX than placebo are shown.
NSABP P-1 Trial: All Adverse Events
% of Women
NOLVADEX
PLACEBO
N=6681
N=6707
Self Reported Symptoms
N=64411
N=64691
Hot Flashes
80
68
Vaginal Discharges
55
35
Vaginal Bleeding
23
22
Laboratory Abnormalities N=65202
N=65352
Platelets decreased
0.7
0.3
Adverse Effects
N=64923
N=64843
Other Toxicities
Mood
11.6
10.8
Infection/Sepsis
6.0
5.1
Constipation
4.4
3.2
Alopecia
5.2
4.4
Skin
5.6
4.7
Allergy
2.5
2.1
1Number with Quality of Life Questionnaires
2Number with Treatment Follow-up Forms
3Number with Adverse Drug Reaction Forms
In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving NOLVADEX and placebo
therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons
NOLVADEX®
(tamoxifen citrate)
Page 28
______________________________________________________________________________________
T-10 10-28 one column
for withdrawing from NOLVADEX and placebo therapy, respectively: Hot flashes (3.1% vs. 1.5%) and
Vaginal Discharge (0.5% vs. 0.1%).
In the NSABP P-1 trial, 8.7 percent and 9.6 percent of participants receiving NOLVADEX and
placebo therapy, respectively withdrew for non-medical reasons.
On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in
80% of women on NOLVADEX. Severe hot flashes occurred in 28% of women on placebo and 45% of
women on NOLVADEX. Vaginal discharge occurred in 35% and 55% of women on placebo and
NOLVADEX respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the
incidence of vaginal bleeding between treatment arms.”
Postmarketing experience: Less frequently reported adverse reactions are vaginal bleeding,
vaginal discharge, menstrual irregularities and skin rash. Usually these have not been of sufficient severity
to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme,
Stevens-Johnson syndrome and bullous pemphigoid have been reported with NOLVADEX therapy.
OVERDOSAGE
Signs observed at the highest doses following studies to determine LD50 in animals were respiratory
difficulties and convulsions.
Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer
patients which specifically determined the maximum tolerated dose of NOLVADEX in evaluating the use
of very high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia,
unsteady gait and dizziness were noted. These symptoms occurred within 3-5 days of beginning
NOLVADEX and cleared within 2-5 days after stopping therapy. No permanent neurologic toxicity was
noted. One patient experienced a seizure several days after NOLVADEX was discontinued and neurotoxic
symptoms had resolved. The causal relationship of the seizure to NOLVADEX therapy is unknown. Doses
given in these patients were all greater than 400 mg/m2 loading dose, followed by maintenance doses of
150 mg/m2 of NOLVADEX given twice a day.
In the same study, prolongation of the QT interval on the electrocardiogram was noted when
patients were given doses higher than 250 mg/m2 loading dose, followed by maintenance doses of 80
mg/m2 of NOLVADEX given twice a day. For a woman with a body surface area of 1.5 m2 the minimal
NOLVADEX®
(tamoxifen citrate)
Page 29
______________________________________________________________________________________
T-10 10-28 one column
loading dose and maintenance doses given at which neurological symptoms and QT changes occurred were
at least 6 fold higher in respect to the maximum recommended dose.
No specific treatment for overdosage is known; treatment must be symptomatic.
DOSAGE AND ADMINISTRATION
For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than 20
mg per day should be given in divided doses (morning and evening).
In three single agent adjuvant studies in women, one 10 mg NOLVADEX tablet was administered
two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in
women with node-negative breast cancer, one 10 mg NOLVADEX tablet was given twice a day for at least
five years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide
additional benefit (see CLINICAL PHARMACOLOGY). In the EBCTCG 1995 overview, the reduction in
recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those
that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg
per day were more effective. Current data from clinical trials support five years of adjuvant NOLVADEX
therapy for patients with breast cancer.
Reduction in Breast Cancer Incidence In High Risk Women: The recommended dose is
NOLVADEX 20 mg daily for five years. There are no data to support the use of NOLVADEX other than
for 5 years. (See CLINICAL PHARMACOLOGY-Clinical Studies - Reduction in Breast Cancer
Incidence in High Risk Women.)
HOW SUPPLIED
10 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 10 mg of tamoxifen
(round, biconvex, uncoated, white tablet identified with NOLVADEX 600 debossed on one side and a
cameo debossed on the other side) are supplied in bottles of 60 tablets and 250 tablets. NDC 0310-0600.
20 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 20 mg of tamoxifen
(round, biconvex, uncoated, white tablet identified with NOLVADEX 604 debossed on one side and a
cameo debossed on the other side) are supplied in bottles of 30 tablets. NDC 0310-0604.
NOLVADEX®
(tamoxifen citrate)
Page 30
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T-10 10-28 one column
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in a well-closed, light-
resistant container.
ZENECA Pharmaceuticals
A Business Unit of ZENECA Inc.
Wilmington, DE 19850-5437 USA
Rev T-10 10/28/98
SIC XXXXX-XX
NOLVADEX10-28-98
|
custom-source
|
2025-02-12T13:44:26.007336
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/17970.pdf', 'application_number': 17970, 'submission_type': 'SUPPL ', 'submission_number': 39}
|
11,104
|
Rev 08-30-02
SIC XXXXX-XX
WARNING - For Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk
for Breast Cancer: Serious and life-threatening events associated with NOLVADEX in the risk
reduction setting (women at high risk for cancer and women with DCIS) include uterine
malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated
from the NSABP P-1 trial (see CLINICAL PHARMACOLOGY-Clinical Studies –
Reduction in Breast Cancer Incidence In High Risk Women). Uterine malignancies consist
of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for
NOLVADEX vs 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years of
0.17 for NOLVADEX vs 0.0 for placebo)*. For stroke, the incidence rate per 1,000 women-
years was 1.43 for NOLVADEX vs 1.00 for placebo**. For pulmonary embolism, the incidence
rate per 1,000 women-years was 0.75 for NOLVADEX versus 0.25 for placebo**.
Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.
Health care providers should discuss the potential benefits versus the potential risks of these
serious events with women at high risk of breast cancer and women with DCIS considering
NOLVADEX to reduce their risk of developing breast cancer.
The benefits of NOLVADEX outweigh its risks in women already diagnosed with breast cancer.
*Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1
study. See WARNINGS: Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma.
**See Table 3 under CLINICAL PHARMACOLOGY-Clinical Studies.
DESCRIPTION
NOLVADEX® (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral
administration. NOLVADEX Tablets are available as:
10 mg Tablets. Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg
of tamoxifen.
20 mg Tablets. Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg
of tamoxifen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOLVADEX 08-30-02
Page 2
Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.
Chemically, NOLVADEX is the trans-isomer of a triphenylethylene derivative. The chemical
name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2-hydroxy-1,2,3-
propanetricarboxylate (1:1). The structural and empirical formulas are:
(C32H37NO8)
Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility
in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.
CLINICAL PHARMACOLOGY
NOLVADEX is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in
animal test systems. The antiestrogenic effects may be related to its ability to compete with
estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat
mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of
already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its
antitumor effects by binding the estrogen receptors.
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for
estrogen receptor protein.
Absorption and Distribution: Following a single oral dose of 20 mg tamoxifen, an average
peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours
after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal
elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-
desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg
tamoxifen given twice daily for 3 months to patients results in average steady-state plasma
concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-
654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of
tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3
months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL),
respectively. After initiation of therapy, steady state concentrations for tamoxifen are achieved in
about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8
weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state,
crossover study of 10 mg NOLVADEX tablets given twice a day vs. a 20 mg NOLVADEX tablet
given once daily, the 20 mg NOLVADEX tablet was bioequivalent to the 10 mg NOLVADEX
tablets.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOLVADEX 08-30-02
Page 3
Metabolism: Tamoxifen is extensively metabolized after oral administration. N-desmethyl
tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-
desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side
chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in
plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-
glycoprotein.
Excretion: Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately
65% of the administered dose was excreted from the body over a period of 2 weeks with fecal
excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates,
with unchanged drug and unconjugated metabolites accounting for less than 30% of the total
fecal radioactivity.
Special Populations: The effects of age, gender and race on the pharmacokinetics of tamoxifen
have not been determined. The effects of reduced liver function on the metabolism and
pharmacokinetics of tamoxifen have not been determined.
Pediatric Patients:
The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a
population pharmacokinetic analysis with sparse samples per patient obtained from 27 female
pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy,
and pharmacokinetics of NOLVADEX in treating McCune-Albright Syndrome. Rich data from
two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast
cancer completed the studies were included in the analysis to determine the structural
pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the
data.
In pediatric patients, an average steady state peak plasma concentration (Css, max) and AUC were
of 187 ng/mL and 4110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after
dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was
approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of
female pediatric patients (2-6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7-10.9
year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was
comparable between the pediatric and adult patients. The safety and efficacy of NOLVADEX
for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty
have not been studied beyond one year of treatment. The long-term effects of NOLVADEX
therapy in girls have not been established. In adults treated with NOLVADEX an increase in
the incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see
BOXED WARNING).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOLVADEX 08-30-02
Page 4
Drug-drug Interactions: In vitro studies showed that erythromycin, cyclosporin, nifedipine and
diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1,
45 and 30 µM, respectively. The clinical significance of these in vitro studies is unknown.
Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-
administered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by
86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen
plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but
not tamoxifen.
Clinical Studies - Metastatic Breast Cancer
Premenopausal Women (NOLVADEX vs. Ablation) - Three prospective, randomized studies
(Ingle, Pritchard, Buchanan) compared NOLVADEX to ovarian ablation (oophorectomy or
ovarian irradiation) in premenopausal women with advanced breast cancer. Although the
objective response rate, time to treatment failure, and survival were similar with both treatments,
the limited patient accrual prevented a demonstration of equivalence. In an overview analysis of
survival data from the 3 studies, the hazard ratio for death (NOLVADEX/ovarian ablation) was
1.00 with two-sided 95% confidence intervals of 0.73 to 1.37. Elevated serum and plasma
estrogens have been observed in premenopausal women receiving NOLVADEX, but the data
from the randomized studies do not suggest an adverse effect of this increase. A limited number
of premenopausal patients with disease progression during NOLVADEX therapy responded to
subsequent ovarian ablation.
Male Breast Cancer - Published results from 122 patients (119 evaluable) and case reports in 16
patients (13 evaluable) treated with NOLVADEX have shown that NOLVADEX is effective for
the palliative treatment of male breast cancer. Sixty-six of these 132 evaluable patients
responded to NOLVADEX which constitutes a 50% objective response rate.
Clinical Studies - Adjuvant Breast Cancer
Overview - The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted
worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and
again in 1995. In 1998, 10-year outcome data were reported for 36,689 women in 55 randomized
trials of adjuvant NOLVADEX using doses of 20-40 mg/day for 1-5+ years. Twenty-five percent
of patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received
about 5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10
fmol/mg), 21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients
with ER positive or unknown breast cancer, 58% were entered into trials comparing
NOLVADEX to no adjuvant therapy and 42% were entered into trials comparing NOLVADEX
in combination with chemotherapy vs. the same chemotherapy alone. Among these patients, 54%
had node positive disease and 46% had node negative disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOLVADEX 08-30-02
Page 5
Among women with ER positive or unknown breast cancer and positive nodes who received
about 5 years of treatment, overall survival at 10 years was 61.4% for NOLVADEX vs. 50.5%
for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for
NOLVADEX vs. 44.5% for control (logrank 2p<0.00001). Among women with ER positive or
unknown breast cancer and negative nodes who received about 5 years of treatment, overall
survival at 10 years was 78.9% for NOLVADEX vs. 73.3% for control (logrank 2p < 0.00001).
The recurrence-free rate at 10 years was 79.2% for NOLVADEX versus 64.3% for control
(logrank 2p<0.00001).
The effect of the scheduled duration of tamoxifen may be described as follows. In women with
ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of
NOLVADEX, the proportional reductions in mortality were 12%, 17% and 26%, respectively
(trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were
21%, 29% and 47% (trend significant at 2p < 0.00001).
Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction in
recurrence was 10% (2p=0.007) for all durations taken together, or 9% (2p=0.02) if contralateral
breast cancers are excluded. The corresponding reduction in mortality was 6% (NS). The effects
of about 5 years of NOLVADEX on recurrence and mortality were similar regardless of age and
concurrent chemotherapy. There was no indication that doses greater than 20 mg per day were
more effective.
Node Positive - Individual Studies - Two studies (Hubay and NSABP B-09) demonstrated an
improved disease-free survival following radical or modified radical mastectomy in
postmenopausal women or women 50 years of age or older with surgically curable breast cancer
with positive axillary nodes when NOLVADEX was added to adjuvant cytotoxic chemotherapy.
In the Hubay study, NOLVADEX was added to "low-dose" CMF (cyclophosphamide,
methotrexate and fluorouracil). In the NSABP B-09 study, NOLVADEX was added to
melphalan [L-phenylalanine mustard (P)] and fluorouracil (F).
In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more
likely to benefit. In the NSABP B-09 study in women age 50-59 years, only women with both
estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a
nonstatistically significant trend toward adverse effect in women with both estrogen and
progesterone receptor levels less than 10 fmol. In women age 60-70 years, there was a trend
toward a beneficial effect of NOLVADEX without any clear relationship to estrogen or
progesterone receptor status.
Three prospective studies (ECOG-1178, Toronto, NATO) using NOLVADEX adjuvantly as a
single agent demonstrated an improved disease-free survival following total mastectomy and
axillary dissection for postmenopausal women with positive axillary nodes compared to
placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOLVADEX 08-30-02
Page 6
Node Negative - Individual Studies - NSABP B-14, a prospective, double-blind, randomized
study, compared NOLVADEX to placebo in women with axillary node-negative, estrogen-
receptor positive (>10 fmol/mg cytosol protein) breast cancer (as adjuvant therapy, following
total mastectomy and axillary dissection, or segmental resection, axillary dissection, and breast
radiation). After five years of treatment, there was a significant improvement in disease-free
survival in women receiving NOLVADEX. This benefit was apparent both in women under age
50 and in women at or beyond age 50.
One additional randomized study (NATO) demonstrated improved disease-free survival for
NOLVADEX compared to no adjuvant therapy following total mastectomy and axillary
dissection in postmenopausal women with axillary node-negative breast cancer. In this study, the
benefits of NOLVADEX appeared to be independent of estrogen receptor status.
Duration of Therapy - In the EBCTCG 1995 overview, the reduction in recurrence and
mortality was greater in those studies that used tamoxifen for about 5 years than in those that
used tamoxifen for a shorter period of therapy.
In the NSABP B-14 trial, in which patients were randomized to NOLVADEX 20 mg/day for 5
years vs. placebo and were disease-free at the end of this 5-year period were offered
rerandomization to an additional 5 years of NOLVADEX or placebo. With 4 years of follow-up
after this rerandomization, 92% of the women that received 5 years of NOLVADEX were alive
and disease-free, compared to 86% of the women scheduled to receive 10 years of NOLVADEX
(p=0.003). Overall survivals were 96% and 94%, respectively (p=0.08). Results of the B-14
study suggest that continuation of therapy beyond 5 years does not provide additional benefit.
A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of
70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up
(HR=1.27, 95% CI 0.87-1.85).
In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of
adjuvant NOLVADEX 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to
be 80% in the patients in the 5-year tamoxifen group, compared with 74% among corresponding
patients in the 2-year treatment group (p=0.03). Disease-free survival at 10 years was 73% in the
5-year group and 67% in the 2-year group (p=0.009). Compared with 2 years of tamoxifen
treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of
contralateral breast cancer at 10 years, but this difference was not statistically significant.
Contralateral Breast Cancer - The incidence of contralateral breast cancer is reduced in breast
cancer patients (premenopausal and postmenopausal) receiving NOLVADEX compared to
placebo. Data on contralateral breast cancer are available from 32,422 out of 36,689 patients in
the 1995 overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG).
In clinical trials with NOLVADEX of 1 year or less, 2 years, and about 5 years duration, the
proportional reductions in the incidence rate of contralateral breast cancer among women
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOLVADEX 08-30-02
Page 7
receiving NOLVADEX were 13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a
significant trend favoring longer tamoxifen duration (2p = 0.008). The proportional reductions in
the incidence of contralateral breast cancer were independent of age and ER status of the primary
tumor. Treatment with about 5 years of NOLVADEX reduced the annual incidence rate of
contralateral breast cancer from 7.6 per 1,000 patients in the control group compared with 3.9 per
1,000 patients in the tamoxifen group.
In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant NOLVADEX 40 mg/day
for 2-5 years, the incidence of second primary breast tumors was reduced 40% (p<0.008) on
tamoxifen compared to control. In the NSABP B-14 trial in which patients were randomized to
NOLVADEX 20 mg/day for 5 years vs. placebo, the incidence of second primary breast cancers
was also significantly reduced (p<0.01). In NSABP B-14, the annual rate of contralateral breast
cancer was 8.0 per 1000 patients in the placebo group compared with 5.0 per 1,000 patients in
the tamoxifen group, at 10 years after first randomization.
Clinical Studies - Ductal Carcinoma in Situ: NSABP B-24, a double-blind, randomized trial
included women with ductal carcinoma in situ (DCIS). This trial compared the addition of
NOLVADEX or placebo to treatment with lumpectomy and radiation therapy for women with
DCIS. The primary objective was to determine whether 5 years of NOLVADEX therapy (20
mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or
contralateral (the opposite) breast.
In this trial 1,804 women were randomized to receive either NOLVADEX or placebo for 5 years:
902 women were randomized to NOLVADEX 10 mg tablets twice a day and 902 women were
randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798
women and the median duration of follow-up was 74 months.
The NOLVADEX and placebo groups were well balanced for baseline demographic and
prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum
dimension, were not palpable, and were detected by mammography alone. Over 60% of the
study population was postmenopausal. In 16% of patients, the margin of the resected specimen
was reported as being positive after surgery. Approximately half of the tumors were reported to
contain comedo necrosis.
For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among
women assigned to NOLVADEX (44 cases - NOLVADEX, 74 cases - placebo; p=0.004; relative
risk (RR)=0.57, 95% CI: 0.39-0.84). No data are available regarding the ER status of the
invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that
reported annually in the SEER data base.
Results are shown in Table 1. For each endpoint the following results are presented: the number
of events and rate per 1,000 women per year for the placebo and NOLVADEX groups; and the
relative risk (RR) and its associated 95% confidence interval (CI) between NOLVADEX and
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placebo. Relative risks less than 1.0 indicate a benefit of NOLVADEX therapy. The limits of
the confidence intervals can be used to assess the statistical significance of the benefits of
NOLVADEX therapy. If the upper limit of the CI is less than 1.0, then a statistically significant
benefit exists.
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Table 1 - Major Outcomes of the NSABP B-24 Trial
Type of
Event
Lumpectomy,
radiotherapy, and placebo
Lumpectomy,
radiotherapy, and
Nolvadex
RR
95% CI limits
No. of
events
Rate per 1000
women per
year
No. of
events
Rate per 1000
women per
year
Invasive
breast cancer
(Primary
endpoint)
74
16.73
44
9.60
0.57
0.39 to 0.84
-Ipsilateral
47
10.61
27
5.90
0.56
0.33 to 0.91
-Contralateral
25
5.64
17
3.71
0.66
0.33 to 1.27
-Side
undetermined
2
--
0
--
--
Secondary Endpoints
DCIS
56
12.66
41
8.95
0.71
0.46 to 1.08
-Ipsilateral
46
10.40
38
8.29
0.88
0.51 to 1.25
-Contralateral
10
2.26
3
0.65
0.29
0.05 to 1.13
All Breast
Cancer Events
129
29.16
84
18.34
0.63
0.47 to 0.83
-All ipsilateral
events
96
21.70
65
14.19
0.65
0.47 to 0.91
-All
contralateral
events
37
8.36
20
4.37
0.52
0.29 to 0.92
Deaths
32
28
Uterine
Malignancies1
4
9
Endometrial
Adenocarcinoma1
4
0.57
8
1.15
Uterine Sarcoma1
0
0.0
1
0.14
Second primary
malignancies
(other than
endometrial
and breast)
30
29
Stroke
2
7
Thromboembol
ic events
(DVT, PE)
5
15
1Updated follow-up data (median 8.1 years)
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Survival was similar in the placebo and NOLVADEX groups. At 5 years from study entry,
survival was 97% for both groups.
Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women
The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized,
placebo-controlled trial with a primary objective to determine whether 5 years of NOLVADEX
therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk
for the disease (See INDICATIONS AND USAGE). Secondary objectives included an
evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone
fractures; and other events that might be associated with the use of NOLVADEX, including:
endometrial cancer, pulmonary embolus, deep vein thrombosis, stroke, and cataract formation
and surgery (See WARNINGS).
The Gail Model was used to calculate predicted breast cancer risk for women who were less than
60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors
were used: age; number of first-degree female relatives with breast cancer; previous breast
biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at
menarche. A 5-year predicted risk of breast cancer of > 1.67% was required for entry into the
trial.
In this trial, 13,388 women of at least 35 years of age were randomized to receive either
NOLVADEX or placebo for five years. The median duration of treatment was 3.5 years. As of
January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of
women randomized to placebo (1,782) and 24% of women randomized to NOLVADEX (1,596)
completed 5 years of therapy. The demographic characteristics of women on the trial with
follow-up data are shown in Table 2.
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Table 2. Demographic Characteristics of Women in the
NSABP P-1 Trial
Characteristic
Placebo
Tamoxifen
#
%
#
%
Age (yrs.)
35-39
184
3
158
2
40-49
2,394
36
2,411
37
50-59
2,011
31
2,019
31
60-69
1,588
24
1,563
24
≥70
393
6
393
6
Age at first live birth(yrs.)
Nulliparous
1,202
18
1,205
18
12-19
915
14
946
15
20-24
2,448
37
2,449
37
25-29
1,399
21
1,367
21
≥30
606
9
577
9
Race
White
6,333
96
6,323
96
Black
109
2
103
2
Other
128
2
118
2
Age at menarche
≥14
1,243
19
1,170
18
12-13
3,610
55
3,610
55
≤11
1,717
26
1,764
27
# of first degree relatives with breast cancer
0
1,584
24
1,525
23
1
3,714
57
3,744
57
2+
1,272
19
1,275
20
Prior Hysterectomy
No
4,173
63.5
4,018
62.4
Yes
2,397
36.5
2,464
37.7
# of previous breast biopsies
0
2,935
45
2,923
45
1
1,833
28
1,850
28
≥2
1,802
27
1,771
27
History of atypical hyperplasia in the breast
No
5,958
91
5,969
91
Yes
612
9
575
9
History of LCIS at entry
No
6,165
94
6,135
94
Yes
405
6
409
6
5-year predicted breast cancer risk (%)
≤2.00
1,646
25
1,626
25
2.01-3.00
2,028
31
2,057
31
3.01-5.00
1,787
27
1,707
26
≥5.01
1,109
17
1,162
18
Total
6,570
100.0
6,544
100.0
Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive
breast cancer was reduced by 44% among women assigned to NOLVADEX (86 cases-
NOLVADEX, 156 cases-placebo; p<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A
reduction in the incidence of breast cancer was seen in each prospectively specified age group (<
49, 50-59, > 60), in women with or without LCIS, and in each of the absolute risk levels
specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ
(DCIS) was seen (23-NOLVADEX, 35-placebo; RR=0.66; 95% CI: 0.39-1.11).
There was no statistically significant difference in the number of myocardial infarctions, severe
angina, or acute ischemic cardiac events between the two groups (61-NOLVADEX, 59-placebo;
RR=1.04, 95% CI: 0.73-1.49).
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No overall difference in mortality (53 deaths in NOLVADEX group vs. 65 deaths in placebo
group) was present. No difference in breast cancer-related mortality was observed (4 deaths in
NOLVADEX group vs. 5 deaths in placebo group).
Although there was a non-significant reduction in the number of hip fractures (9 on
NOLVADEX, 20 on placebo) in the NOLVADEX group, the number of wrist fractures was
similar in the two treatment groups (69 on NOLVADEX, 74 on placebo). No information
regarding bone mineral density or other markers of osteoporosis is available.
The risks of NOLVADEX therapy include endometrial cancer, DVT, PE, stroke, cataract
formation and cataract surgery (See Table 3). In the NSABP P-1 trial, 33 cases of endometrial
cancer were observed in the NOLVADEX group vs. 14 in the placebo group (RR=2.48, 95% CI:
1.27-4.92). Deep vein thrombosis was observed in 30 women receiving NOLVADEX vs. 19 in
women receiving placebo (RR=1.59, 95% CI: 0.86-2.98). Eighteen cases of pulmonary embolism
were observed in the NOLVADEX group vs. 6 in the placebo group (RR=3.01, 95% CI: 1.15-
9.27). There were 34 strokes on the NOLVADEX arm and 24 on the placebo arm (RR=1.42;
95% CI 0.82-2.51). Cataract formation in women without cataracts at baseline was observed in
540 women taking NOLVADEX vs. 483 women receiving placebo (RR=1.13, 95% CI: 1.00-
1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women
taking NOLVADEX vs. 129 women receiving placebo (RR=1.51, 95% CI 1.21-1.89) (See
WARNINGS).
Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the
following results are presented: the number of events and rate per 1000 women per year for the
placebo and NOLVADEX groups; and the relative risk (RR) and its associated 95% confidence
interval (CI) between NOLVADEX and placebo. Relative risks less than 1.0 indicate a benefit of
NOLVADEX therapy. The limits of the confidence intervals can be used to assess the statistical
significance of the benefits or risks of NOLVADEX therapy. If the upper limit of the CI is less
than 1.0, then a statistically significant benefit exists.
For most participants, multiple risk factors would have been required for eligibility. This table
considers risk factors individually, regardless of other co-existing risk factors, for women who
developed breast cancer. The 5-year predicted absolute breast cancer risk accounts for multiple
risk factors in an individual and should provide the best estimate of individual benefit (See
INDICATIONS AND USAGE).
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Table 3: Major Outcomes of the NSABP P-1 Trial
# OF EVENTS
RATE/1000 WOMEN/YEAR
95% CI
TYPE OF EVENT
PLACEBO NOLVADEX PLACEBO NOLVADEX RR LIMITS
Invasive Breast Cancer
156
86
6.49
3.58
0.56
0.43-0.72
Age <49
59
38
6.34
4.11
0.65
0.43-0.98
Age 50-59
46
25
6.31
3.53
0.56
0.35-0.91
Age ≥60
51
23
7.17
3.22
0.45
0.27-0.74
Risk Factors for Breast Cancer
History, LCIS
No
140
78
6.23
3.51
0.56
0.43-0.74
Yes
16
8
12.73
6.33
0.50
0.21-1.17
History, Atypical Hyperplasia
No
138
84
6.37
3.89
0.61
0.47-0.80
Yes
18
2
8.69
1.05
0.12
0.03-0.52
No. First Degree Relatives
0
32
17
5.97
3.26
0.55
0.30-0.98
1
80
45
5.81
3.31
0.57
0.40-0.82
2
35
18
8.92
4.67
0.52
0.30-0.92
≥3
9
6
13.33
7.58
0.57
0.20-1.59
5-Year Predicted Breast Cancer Risk
(as calculated by the Gail Model)
<2.00%
31
13
5.36
2.26
0.42
0.22-0.81
2.01-3.00%
39
28
5.25
3.83
0.73
0.45-1.18
3.01-5.00%
36
26
5.37
4.06
0.76
0.46-1.26
≥5.00%
50
19
13.15
4.71
0.36
0.21-0.61
DCIS
35
23
1.47
0.97
0.66
0.39-1.11
Fractures (protocol-specified sites)
921
761
3.87
3.20
0.61
0.83-1.12
Hip
20
9
0.84
0.38
0.45
0.18-1.04
Wrist2
74
69
3.11
2.91
0.93
0.67-1.29
Total Ischemic Events
59
61
2.47
2.57
1.04
0.71-1.51
Myocardial Infarction
27
27
1.13
1.13
1.00
0.57-1.78
Fatal
8
7
0.33
0.29
0.88
0.27-2.77
Nonfatal
19
20
0.79
0.84
1.06
0.54-2.09
Angina3
12
12
0.50
0.50
1.00
0.41-2.44
Acute Ischemic Syndrome4
20
22
0.84
0.92
1.11
0.58-2.13
Uterine
Malignancies (among
women with an intact uterus) 10
17
57
Endometrial Adenocarcinoma10
17
53
0.71
2.20
Uterine Sarcoma10
0
4
0.0
0.17
Stroke5
24
34
1.00
1.43
1.42
0.82-2.51
Transient Ischemic Attack
21
18
0.88
0.75
0.86
0.43-1.70
Pulmonary Emboli6
6
18
0.25
0.75
3.01
1.15-9.27
Deep-Vein Thrombosis7
19
30
0.79
1.26
1.59
0.86-2.98
Cataracts Developing on Study8
483
540
22.51
25.41
1.13
1.00-1.28
Underwent Cataract Surgery8
63
101
21.83
4.57
1.62
1.18-2.22
Underwent Cataract Surgery9
129
201
5.44
8.56
1.58
1.26-1.97
1Two women had hip and wrist fractures
2 Includes Colles' and other lower radius fractures
3Requiring angioplasty or CABG
4New Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring hospitalization without surgery
5Seven cases were fatal; three in the placebo group and four in the NOLVADEX group
6Three cases in the NOLVADEX group were fatal
7All but three cases in each group required hospitalization
8Based on women without cataracts at baseline (6,230-Placebo, 6,199-NOLVADEX)
9All women (6,707-Placebo, 6,681-NOLVADEX)
10Updated long-term follow-up data (median 6.9 years) from NSABP P-1 study added after cut-off for the other information in this table.
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Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes
tumor size, nodal status, ER status. NOLVADEX decreased the incidence of small estrogen
receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or
larger tumors.
Table 4: Characteristics of Breast Cancer in NSABP P-1 Trial
Staging Parameter
Placebo
Tamoxifen
Total
N=156
N=86
N=242
Tumor size:
T1
117
60
177
T2
28
20
48
T3
7
3
10
T4
1
2
3
Unknown
3
1
4
Nodal status:
Negative
103
56
159
1-3 positive nodes
29
14
43
≥ 4 positive nodes
10
12
22
Unknown
14
4
18
Stage:
I
88
47
135
II: node negative
15
9
24
II: node positive
33
22
55
III
6
4
10
IV
21
1
3
Unknown
12
3
15
Estrogen receptor:
Positive
115
38
153
Negative
27
36
63
Unknown
14
12
26
1 One participant presented with a suspicious bone scan but did not have documented metastases. She subsequently died of metastatic breast cancer.
Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of
tamoxifen in reducing breast cancer incidence have been reported.
The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35
and 70, who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or
matching placebo for 5 years. The primary endpoints were occurrence of, and death from,
invasive breast cancer. Women without any specific risk factors for breast cancer were to be
entered. Between 1992 and 1997, 5408 women were randomized. Hormone Replacement
Therapy (HRT) was used in 14% of participants. The trial closed in 1997 due to the large
number of dropouts during the first year of treatment (26%). After 46 months of follow-up there
were 22 breast cancers in women on placebo and 19 in women on tamoxifen. Although no
decrease in breast cancer incidence was observed, there was a trend for a reduction in breast
cancer among women receiving protocol therapy for at least 1 year (19-placebo, 11- tamoxifen).
The small numbers of participants along with the low level of risk in this otherwise healthy group
precluded an adequate assessment of the effect of tamoxifen in reducing the incidence of breast
cancer.
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The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT
was begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial
was subsequently extended to a pilot trial to accrue additional participants to further assess the
safety of tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986
and 1996; they were selected on the basis of a family history of breast cancer. HRT was used in
40% of participants. In this trial, with a 70-month median follow-up, 34 and 36 breast cancers (8
noninvasive, 4 on each arm) were observed among women on tamoxifen and placebo,
respectively. Patients in this trial were younger than those in the NSABP P-1 trial and may have
been more likely to develop ER (-) tumors, which are unlikely to be reduced in number by
tamoxifen therapy. Although women were selected on the basis of family history and were
thought to have a high risk of breast cancer, few events occurred, reducing the statistical power
of the study. These factors are potential reasons why the RMT may not have provided an
adequate assessment of the effectiveness of tamoxifen in reducing the incidence of breast cancer.
In these trials, an increased number of cases of deep vein thrombosis, pulmonary embolus,
stroke, and endometrial cancer were observed on the tamoxifen arm compared to the placebo
arm. The frequency of events was consistent with the safety data observed in the NSABP P-1
trial.
Clinical Studies – McCune-Albright Syndrome: A single, uncontrolled multicenter trial of
NOLVADEX 20 mg once a day was conducted in a heterogeneous group of girls with McCune-
Albright Syndrome and precocious puberty manifested by physical signs of pubertal
development, episodes of vaginal bleeding and/or advanced bone age (bone age of at least 12
months beyond chronological age). Twenty-eight female pediatric patients, aged 2 to 10 years,
were treated for up to 12 months. Effect of treatment on frequency of vaginal bleeding, bone age
advancement, and linear growth rate was assessed relative to prestudy baseline. NOLVADEX
treatment was associated with a 50% reduction in frequency of vaginal bleeding episodes by
patient or family report (mean annualized frequency of 3.56 episodes at baseline and 1.73
episodes on-treatment). Among the patients who reported vaginal bleeding during the pre-study
period, 62% (13 out of 21 patients) reported no bleeding for a 6-month period and 33% (7 out of
21 patients) reported no vaginal bleeding for the duration of the trial. Not all patients improved
on treatment and a few patients not reporting vaginal bleeding in the 6 months prior to
enrollment reported menses on treatment. NOLVADEX therapy was associated with a reduction
in mean rate of increase of bone age. Individual responses with regard to bone age advancement
were highly heterogeneous. Linear growth rate was reduced during the course of NOLVADEX
treatment in a majority of patients (mean change of 1.68 cm/year relative to baseline; change
from 7.47 cm/year at baseline to 5.79 cm/year on study). This change was not uniformly seen
across all stages of bone maturity; all recorded response failures occurred in patients with bone
ages less than 7 years at screening.
Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-
year study. A causal relationship has not been established; however, as an increase in the
incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated
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with NOLVADEX (see BOXED WARNING), continued monitoring of McCune-Albright
patients treated with NOLVADEX for long-term uterine effects is recommended. The safety
and efficacy of NOLVADEX for girls aged two to 10 years with McCune-Albright
Syndrome and precocious puberty have not been studied beyond one year of treatment.
The long-term effects of NOLVADEX therapy in girls have not been established.
INDICATIONS AND USAGE
Metastatic Breast Cancer: NOLVADEX is effective in the treatment of metastatic breast
cancer in women and men. In premenopausal women with metastatic breast cancer,
NOLVADEX is an alternative to oophorectomy or ovarian irradiation. Available evidence
indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from
NOLVADEX therapy.
Adjuvant Treatment of Breast Cancer: NOLVADEX is indicated for the treatment of node-
positive breast cancer in postmenopausal women following total mastectomy or segmental
mastectomy, axillary dissection, and breast irradiation. In some NOLVADEX adjuvant studies,
most of the benefit to date has been in the subgroup with four or more positive axillary nodes.
NOLVADEX is indicated for the treatment of axillary node-negative breast cancer in women
following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation.
The estrogen and progesterone receptor values may help to predict whether adjuvant
NOLVADEX therapy is likely to be beneficial.
NOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant
NOLVADEX therapy for breast cancer.
Ductal Carcinoma in Situ (DCIS): In women with DCIS, following breast surgery and
radiation, NOLVADEX is indicated to reduce the risk of invasive breast cancer (see BOXED
WARNING at the beginning of the label). The decision regarding therapy with NOLVADEX for
the reduction in breast cancer incidence should be based upon an individual assessment of the
benefits and risks of NOLVADEX therapy.
Current data from clinical trials support five years of adjuvant NOLVADEX therapy for patients
with breast cancer.
Reduction in Breast Cancer Incidence in High Risk Women: NOLVADEX is indicated to
reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was
shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five
percent of the participants received drug for 5 years. The longer-term effects are not known. In
this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see
BOXED WARNING at the beginning of the label).
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NOLVADEX is indicated only for high-risk women. “High risk” is defined as women at least 35
years of age with a 5-year predicted risk of breast cancer > 1.67%, as calculated by the Gail
Model.
Examples of combinations of factors predicting a 5-year risk > 1.67% are:
Age 35 or older and any of the following combination of factors:
• One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a
history of a breast biopsy showing atypical hyperplasia; or
• At least 2 first degree relatives with a history of breast cancer, and a personal history of at
least one breast biopsy; or
• LCIS
Age 40 or older and any of the following combination of factors:
• One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first
live birth 25 or older, and age at menarche 11 or younger; or
• At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or
younger; or
• One first degree relative with a history of breast cancer, and a personal history of a breast
biopsy showing atypical hyperplasia.
Age 45 or older and any of the following combination of factors:
• At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or
younger; or
• One first degree relative with a history of breast cancer with a personal history of a benign
breast biopsy, age at menarche 11 or less and age at first live birth 20 or more.
Age 50 or older and any of the following combination of factors:
• At least 2 first degree relatives with a history of breast cancer; or
• History of one breast biopsy showing atypical hyperplasia, and age at first live birth 30 or
older and age at menarche 11 or less; or
• History of at least two breast biopsies with a history of atypical hyperplasia, and age at first
live birth 30 or more.
Age 55 or older and any of the following combination of factors:
• One first degree relative with a history of breast cancer with a personal history of a benign
breast biopsy, and age at menarche 11 or less; or
• History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first
live birth 20 or older.
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Age 60 or older and:
• 5-year predicted risk of breast cancer > 1.67%, as calculated by the Gail Model.
For women whose risk factors are not described in the above examples, the Gail Model is
necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail
Model Risk Assessment Tool by dialing 1-800-544-2007.
There are no data available regarding the effect of NOLVADEX on breast cancer incidence in
women with inherited mutations (BRCA1, BRCA2).
After an assessment of the risk of developing breast cancer, the decision regarding therapy with
NOLVADEX for the reduction in breast cancer incidence should be based upon an individual
assessment of the benefits and risks of NOLVADEX therapy. In the NSABP P-1 trial,
NOLVADEX treatment lowered the risk of developing breast cancer during the follow-up period
of the trial, but did not eliminate breast cancer risk (See Table 3 in CLINICAL
PHARMACOLOGY).
CONTRAINDICATIONS
NOLVADEX is contraindicated in patients with known hypersensitivity to the drug or any of its
ingredients.
Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS:
NOLVADEX is contraindicated in women who require concomitant coumarin-type anticoagulant
therapy or in women with a history of deep vein thrombosis or pulmonary embolus.
WARNINGS
Effects in Metastatic Breast Cancer Patients: As with other additive hormonal therapy
(estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with
bone metastases within a few weeks of starting treatment with NOLVADEX. If hypercalcemia
does occur, appropriate measures should be taken and, if severe, NOLVADEX should be
discontinued.
Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma: An increased incidence of
uterine malignancies has been reported in association with NOLVADEX treatment. The
underlying mechanism is unknown, but may be related to the estrogen-like effect of
NOLVADEX. Most uterine malignancies seen in association with NOLVADEX are classified as
adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant
mixed mullerian tumors, have also been reported. Uterine sarcoma is generally associated with a
higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma
has been reported to occur more frequently among long-term users (> 2 years) of NOLVADEX
than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma)
have been fatal.
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In the NSABP P-1 trial, among participants randomized to NOLVADEX there was a statistically
significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial
cancer, compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI:
1.27-4.92). The 33 cases in participants receiving NOLVADEX were FIGO Stage I, including 20
IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13
were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on Nolvadex and 1
on placebo received postoperative radiation therapy in addition to surgery. This increase was
primarily observed among women at least 50 years of age at the time of randomization (26 cases
of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo
(RR=4.50, 95% CI: 1.78-13.16). Among women ≤ 49 years of age at the time of randomization
there were 7 cases of invasive endometrial cancer, compared to 8 cases among participants
randomized to placebo (RR=0.94, 95% CI: 0.28-2.89). If age at the time of diagnosis is
considered, there were 4 cases of endometrial cancer among participants < 49 randomized to
NOLVADEX compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-
12.0). For women > 50 at the time of diagnosis, there were 29 cases among participants
randomized to NOLVADEX compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3-
4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger
women. Most (29 of 33 cases in the NOLVADEX group) endometrial cancers were diagnosed in
symptomatic women, although 5 of 33 cases in the NOLVADEX group occurred in
asymptomatic women. Among women receiving NOLVADEX the events appeared between 1
and 61 months (average=32 months) from the start of treatment.
In an updated review of long-term data (median length of total follow-up is 6.9 years, including
blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1
risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was
increased in women taking NOLVADEX. Endometrial adenocarcinoma was reported in 53
women randomized to NOLVADEX (52 cases of FIGO Stage I, and 1 Stage III endometrial
adenocarcinoma) and 17 women randomized to placebo (16 cases of FIGO Stage I and 1 case of
FIGO Stage II endometrial adenocarcinoma) (incidence per 1,000 women-years of 2.20 and 0.71,
respectively). Some patients received post-operative radiation therapy in addition to surgery.
Uterine sarcomas were reported in 4 women randomized to NOLVADEX (2 FIGO I, 1 FIGO II,
1 FIGO III. The FIGO I cases were a sarcoma and a MMMT. The FIGO II was a MMMT and
the FIGO III was a sarcoma) and 0 patients randomized to placebo (incidence per 1,000 women-
years of 0.17 and 0.0, respectively). A similar increased incidence in endometrial
adenocarcinoma and uterine sarcoma was observed among women receiving NOLVADEX in
five other NSABP clinical trials.
Any patient receiving or who has previously received NOLVADEX who reports abnormal
vaginal bleeding should be promptly evaluated. Patients receiving or who have previously
received NOLVADEX should have annual gynecological examinations and they should promptly
inform their physicians if they experience any abnormal gynecological symptoms, eg, menstrual
irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or
pressure.
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In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate
compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5%
without sampling) for women with an intact uterus. There are no data to suggest that routine
endometrial sampling in asymptomatic women taking NOLVADEX to reduce the incidence of
breast cancer would be beneficial.
Non-Malignant Effects on the Uterus: An increased incidence of endometrial changes
including hyperplasia and polyps have been reported in association with NOLVADEX treatment.
The incidence and pattern of this increase suggest that the underlying mechanism is related to the
estrogenic properties of NOLVADEX.
There have been a few reports of endometriosis and uterine fibroids in women receiving
NOLVADEX. The underlying mechanism may be due to the partial estrogenic effect of
NOLVADEX. Ovarian cysts have also been observed in a small number of premenopausal
patients with advanced breast cancer who have been treated with NOLVADEX.
NOLVADEX has been reported to cause menstrual irregularity or amenorrhea.
Thromboembolic Effects of NOLVADEX: There is evidence of an increased incidence of
thromboembolic events, including deep vein thrombosis and pulmonary embolism, during
NOLVADEX therapy. When NOLVADEX is coadminstered with chemotherapy, there may be a
further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the
risks and benefits of NOLVADEX should be carefully considered in women with a history of
thromboembolic events.
Data from the NSABP P-1 trial show that participants receiving NOLVADEX without a history
of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-
NOLVADEX, 6-placebo, RR=3.01, 95% CI: 1.15- 9.27). Three of the pulmonary emboli, all in
the NOLVADEX arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism
occurred in women at least 50 years of age at randomization. Among women receiving
NOLVADEX, the events appeared between 2 and 60 months (average=27 months) from the start
of treatment.
In this same population, a non-statistically significant increase in deep vein thrombosis (DVT)
was seen in the NOLVADEX group (30-NOLVADEX, 19-placebo; RR=1.59, 95% CI: 0.86-
2.98). The same increase in relative risk was seen in women < 49 and in women > 50, although
fewer events occurred in younger women. Women with thromboembolic events were at risk for a
second related event (7 out of 25 women on placebo, 5 out of 48 women on NOLVADEX) and
were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on
NOLVADEX). Among women receiving NOLVADEX, deep vein thrombosis events occurred
between 2 and 57 months (average=19 months) from the start of treatment.
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There was a non-statistically significant increase in stroke among patients randomized to
NOLVADEX (24-Placebo; 34-NOLVADEX; RR=1.42; 95% CI 0.82-2.51). Six of the 24 strokes
in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the
NOLVADEX group were categorized as hemorrhagic. Seventeen of the 34 strokes in the
NOLVADEX group were considered occlusive and 7 were considered to be of unknown
etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of
unknown etiology. Among these strokes 3 strokes in the placebo group and 4 strokes in the
NOLVADEX group were fatal. Eighty-eight percent of the strokes occurred in women at least 50
years of age at the time of randomization. Among women receiving NOLVADEX, the events
occurred between 1 and 63 months (average=30 months) from the start of treatment.
Effects on the liver: Liver cancer: In the Swedish trial using adjuvant NOLVADEX 40 mg/day
for 2-5 years, 3 cases of liver cancer have been reported in the NOLVADEX-treated group vs. 1
case in the observation group (See PRECAUTIONS-Carcinogenesis). In other clinical trials
evaluating NOLVADEX, no cases of liver cancer have been reported to date.
One case of liver cancer was reported in NSABP P-1 in a participant randomized to
NOLVADEX.
Effects on the liver: Non-malignant effects: NOLVADEX has been associated with changes in
liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities
including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases
included fatalities. In most reported cases the relationship to NOLVADEX is uncertain.
However, some positive rechallenges and dechallenges have been reported.
In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin,
alkaline phosphatase) were observed (10 on placebo and 6 on NOLVADEX). Serum lipids were
not systematically collected.
Other cancers: A number of second primary tumors, occurring at sites other than the
endometrium, have been reported following the treatment of breast cancer with NOLVADEX in
clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-
uterine) cancers among patients receiving NOLVADEX. Whether an increased risk for other
(non-uterine) cancers is associated with NOLVADEX is still uncertain and continues to be
evaluated.
Effects on the Eye: Ocular disturbances, including corneal changes, decrement in color vision
perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving
NOLVADEX. An increased incidence of cataracts and the need for cataract surgery have been
reported in patients receiving NOLVADEX.
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In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts
among those women without cataracts at baseline (540-NOLVADEX; 483-placebo; RR=1.13,
95% CI: 1.00-1.28) was observed. Among these same women, NOLVADEX was associated
with an increased risk of having cataract surgery (101-NOLVADEX; 63-placebo; RR=1.62, 95%
CI 1.17-2.25) (See Table 3 in CLINICAL PHARMACOLOGY). Among all women on the
trial (with or without cataracts at baseline), NOLVADEX was associated with an increased risk
of having cataract surgery (201-NOLVADEX; 129-placebo; RR=1.51, 95% CI 1.21-1.89). Eye
examinations were not required during the study. No other conclusions regarding non-cataract
ophthalmic events can be made.
Pregnancy Category D: NOLVADEX may cause fetal harm when administered to a pregnant
woman. Women should be advised not to become pregnant while taking NOLVADEX or within
2 months of discontinuing NOLVADEX and should use barrier or nonhormonal contraceptive
measures if sexually active. Tamoxifen does not cause infertility, even in the presence of
menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic
properties of the drug. In reproductive studies in rats at dose levels equal to or below the human
dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In
addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below
those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal
death or retarded in utero growth were observed, with slower learning behavior in some rat pups
when compared to historical controls. Several pregnant marmosets were dosed with 10
mg/kg/day (about 2-fold the daily maximum recommended human dose on a mg/m2 basis) during
organogenesis or in the last half of pregnancy. No deformations were seen and, although the
dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy
showed no evidence of teratogenic malformations.
In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4-fold
the daily maximum recommended human dose on a mg/m2 basis) caused changes in both sexes
that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the
clinical relevance of these changes is unknown, some of these changes, especially vaginal
adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in
utero and who have a 1 in 1000 risk of developing clear-cell adenocarcinoma of the vagina or
cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or
clear-cell adenocarcinoma of the vagina or cervix, in young women. However, only a small
number of young women have been exposed to tamoxifen in utero, and a smaller number have
been followed long enough (to age 15-20) to determine whether vaginal or cervical neoplasia
could occur as a result of this exposure.
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There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have
been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and
fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes
pregnant while taking this drug, or within approximately two months after discontinuing therapy,
the patient should be apprised of the potential risks to the fetus including the potential long-term
risk of a DES-like syndrome.
Reduction in Breast Cancer Incidence in High Risk Women - Pregnancy Category D: For
sexually active women of child-bearing potential, NOLVADEX therapy should be initiated
during menstruation. In women with menstrual irregularity, a negative B-HCG immediately
prior to the initiation of therapy is sufficient (See PRECAUTIONS-Information for Patients -
Reduction in Breast Cancer Incidence in High Risk Women).
PRECAUTIONS
General: Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have
been occasionally reported in patients taking NOLVADEX for breast cancer. In patients with
significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if
these episodes are due to NOLVADEX therapy. Leukopenia has been observed, sometimes in
association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia
and pancytopenia in patients receiving NOLVADEX; this can sometimes be severe.
In the NSABP P-1 trial, 6 women on NOLVADEX and 2 on placebo experienced grade 3-4
drops in platelet counts (≤50,000/mm3).
Information for Patients:
Reduction in Invasive Breast Cancer and DCIS in Women with DCIS: Women with DCIS
treated with lumpectomy and radiation therapy who are considering NOLVADEX to reduce the
incidence of a second breast cancer event should assess the risks and benefits of therapy, since
treatment with NOLVADEX decreased the incidence of invasive breast cancer, but has not been
shown to affect survival (See Table 1 in CLINICAL PHARMACOLOGY).
Reduction in Breast Cancer Incidence in High Risk Women: Women who are at high risk for
breast cancer can consider taking NOLVADEX therapy to reduce the incidence of breast cancer.
Whether the benefits of treatment are considered to outweigh the risks depends on a woman's
personal health history and on how she weighs the benefits and risks. NOLVADEX therapy to
reduce the incidence of breast cancer may therefore not be appropriate for all women at high risk
for breast cancer. Women who are considering NOLVADEX therapy should consult their health
care professional for an assessment of the potential benefits and risks prior to starting therapy for
reduction in breast cancer incidence (See Table 3 in CLINICAL PHARMACOLOGY).
Women should understand that NOLVADEX reduces the incidence of breast cancer, but may not
eliminate risk. NOLVADEX decreased the incidence of small estrogen receptor positive tumors,
but did not alter the incidence of estrogen receptor negative tumors or larger tumors. In women
with breast cancer who are at high risk of developing a second breast cancer, treatment with
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NOLVADEX 08-30-02
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about 5 years of NOLVADEX reduced the annual incidence rate of a second breast cancer by
approximately 50%.
Women who are pregnant or who plan to become pregnant should not take NOLVADEX to
reduce her risk of breast cancer. Effective nonhormonal contraception must be used by all
premenopausal women taking NOLVADEX and for approximately two months after
discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in the
presence of menstrual irregularity. For sexually active women of child-bearing potential,
NOLVADEX therapy should be initiated during menstruation. In women with menstrual
irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient (See
WARNINGS-Pregnancy Category D).
Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed
no difference in the number of breast cancer cases between the tamoxifen and placebo arms.
These studies had trial designs that differed from that of NSABP P-1, were smaller than NSABP
P-1, and enrolled women at a lower risk for breast cancer than those in P-1.
Monitoring During NOLVADEX Therapy: Women taking or having previously taken
NOLVADEX should be instructed to seek prompt medical attention for new breast lumps,
vaginal bleeding, gynecologic symptoms (menstrual irregularities, changes in vaginal discharge,
or pelvic pain or pressure), symptoms of leg swelling or tenderness, unexplained shortness of
breath, or changes in vision. Women should inform all care providers, regardless of the reason
for evaluation, that they take NOLVADEX.
Women taking NOLVADEX to reduce the incidence of breast cancer should have a breast
examination, a mammogram, and a gynecologic examination prior to the initiation of therapy.
These studies should be repeated at regular intervals while on therapy, in keeping with good
medical practice. Women taking NOLVADEX as adjuvant breast cancer therapy should follow
the same monitoring procedures as for women taking NOLVADEX for the reduction in the
incidence of breast cancer. Women taking NOLVADEX as treatment for metastatic breast
cancer should review this monitoring plan with their care provider and select the appropriate
modalities and schedule of evaluation.
Laboratory Tests: Periodic complete blood counts, including platelet counts, and periodic liver
function tests should be obtained.
Drug Interactions: When NOLVADEX is used in combination with coumarin-type
anticoagulants, a significant increase in anticoagulant effect may occur. Where such
coadministration exists, careful monitoring of the patient's prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were
ineligible for participation in the trial (See CONTRAINDICATIONS).
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There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in
combination with NOLVADEX.
Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on
metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other
drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-
desmethyl tamoxifen plasma concentrations have been shown to be reduced when
coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated
metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4
inducing agents have not been studied to confirm this effect.
One patient receiving NOLVADEX with concomitant phenobarbital exhibited a steady state
serum level of tamoxifen lower than that observed for other patients (ie, 26 ng/mL vs. mean
value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin
induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of
tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen
plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but
not tamoxifen.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-
desmethyl tamoxifen.
Drug/Laboratory Testing Interactions: During postmarketing surveillance, T4 elevations
were reported for a few postmenopausal patients which may be explained by increases in thyroid-
binding globulin. These elevations were not accompanied by clinical hyperthyroidism.
Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect
on Pap smears have been infrequently seen in postmenopausal patients given NOLVADEX.
In the postmarketing experience with NOLVADEX, infrequent cases of hyperlipidemias have
been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in
patients with pre-existing hyperlipidemias (See ADVERSE REACTIONS-Postmarketing
experience section).
Carcinogenesis: A conventional carcinogenesis study in rats at doses of 5, 20, and 35
mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a
mg/m2 basis) administered by oral gavage for up to 2 years) revealed a significant increase in
hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater
among rats administered 20 or 35 mg/kg/day (69%) compared to those administered 5 mg/kg/day
(14%). In a separate study, rats were administered tamoxifen at 45 mg/kg/day (about nine-fold
the daily maximum recommended human dose on a mg/m2 basis); hepatocellular neoplasia was
exhibited at 3 to 6 months.
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Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two
separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen
for 13 to 15 months at doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the
daily recommended human dose on a mg/m2 basis).
Mutagenesis: No genotoxic potential was found in a conventional battery of in vivo and in vitro
tests with pro- and eukaryotic test systems with drug metabolizing systems. However, increased
levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured
human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus
formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings,
tamoxifen is genotoxic in rodent and human MCL-5 cells.
Impairment of Fertility: Tamoxifen produced impairment of fertility and conception in female
rats at doses of 0.04 mg/kg/day (about 0.01-fold the daily maximum recommended human dose
on a mg/m2 basis) when dosed for two weeks prior to mating through day 7 of pregnancy. At this
dose, fertility and reproductive indices were markedly reduced with total fetal mortality. Fetal
mortality was also increased at doses of 0.16 mg/kg/day (about 0.03-fold the daily maximum
recommended human dose on a mg/m2 basis) when female rats were dosed from days 7-17 of
pregnancy. Tamoxifen produced abortion, premature delivery and fetal death in rabbits
administered doses equal to or greater than 0.125 mg/kg/day (about 0.05-fold the daily maximum
recommended human dose on a mg/m2 basis). There were no teratogenic changes in either rats
or rabbits.
Pregnancy Category D: See WARNINGS.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious adverse reactions in
nursing infants from NOLVADEX, a decision should be made whether to discontinue nursing or
to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: The safety and efficacy of NOLVADEX for girls aged two to 10 years with
McCune-Albright Syndrome and precocious puberty have not been studied beyond one
year of treatment. The long-term effects of NOLVADEX therapy for girls have not been
established. In adults treated with NOLVADEX, an increase in the incidence of uterine
malignancies, stroke and pulmonary embolism has been noted (see BOXED WARNING, and
CLINICAL PHARMACOLOGY-Clinical Studies-McCune-Albright Syndrome subsection).
Geriatric Use: In the NSABP P-1 trial, the percentage of women at least 65 years of age was
16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast
cancer incidence was seen among participants in each of the subsets: A total of 28 and 10
invasive breast cancers were seen among participants 65 and older in the placebo and
NOLVADEX groups, respectively. Across all other outcomes, the results in this subset reflect
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the results observed in the subset of women at least 50 years of age. No overall differences in
tolerability were observed between older and younger patients (See CLINICAL
PHARMACOLOGY - Clinical Studies - Reduction in Breast Cancer Incidence in High
Risk Women section).
In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at
least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast
cancers were seen among participants 65 and older in the placebo and NOLVADEX groups,
respectively. This subset is too small to reach any conclusions on efficacy. Across all other
endpoints, the results in this subset were comparable to those of younger women enrolled in this
trial. No overall differences in tolerability were observed between older and younger patients.
ADVERSE REACTIONS
Adverse reactions to NOLVADEX are relatively mild and rarely severe enough to require
discontinuation of treatment in breast cancer patients.
Continued clinical studies have resulted in further information which better indicates the
incidence of adverse reactions with NOLVADEX as compared to placebo.
Metastatic Breast Cancer: Increased bone and tumor pain and, also, local disease flare have
occurred, which are sometimes associated with a good tumor response. Patients with increased
bone pain may require additional analgesics. Patients with soft tissue disease may have sudden
increases in the size of preexisting lesions, sometimes associated with marked erythema within
and surrounding the lesions and/or the development of new lesions. When they occur, the bone
pain or disease flare are seen shortly after starting NOLVADEX and generally subside rapidly.
In patients treated with NOLVADEX for metastatic breast cancer, the most frequent adverse
reaction to NOLVADEX is hot flashes.
Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema,
distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning
and/or partial hair loss, and vaginal dryness.
Premenopausal Women: The following table summarizes the incidence of adverse reactions
reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which
compared NOLVADEX therapy to ovarian ablation in premenopausal patients with metastatic
breast cancer.
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NOLVADEX 08-30-02
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OVARIAN
NOLVADEX
ABLATION
All Effects
All Effects
% of Women
% of Women
Adverse Reactions*
n = 104
n = 100
Flush
33
46
Amenorrhea
16
69
Altered Menses
13
5
Oligomenorrhea
9
1
Bone Pain
6
6
Menstrual Disorder
6
4
Nausea
5
4
Cough/Coughing
4
1
Edema
4
1
Fatigue
4
1
Musculoskeletal Pain
3
0
Pain
3
4
Ovarian Cyst(s)
3
2
Depression
2
2
Abdominal Cramps
1
2
Anorexia
1
2
*Some women had more than one adverse reaction.
Male Breast Cancer: NOLVADEX is well tolerated in males with breast cancer. Reports from
the literature and case reports suggest that the safety profile of NOLVADEX in males is similar
to that seen in women. Loss of libido and impotence have resulted in discontinuation of
tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH,
FSH, testosterone and estrogen levels were elevated. No significant clinical changes were
reported.
Adjuvant Breast Cancer: In the NSABP B-14 study, women with axillary node-negative breast
cancer were randomized to 5 years of NOLVADEX 20 mg/day or placebo following primary
surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8
years) showing adverse events more common on NOLVADEX than on placebo. The incidence
of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs.
19%) were higher with NOLVADEX compared with placebo. All other adverse effects occurred
with similar frequency in the 2 treatment groups, with the exception of thrombotic events; a
higher incidence was seen in NOLVADEX-treated patients (through 5 years, 1.7% vs. 0.4%).
Two of the patients treated with NOLVADEX who had thrombotic events died.
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NOLVADEX 08-30-02
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NSABP B-14 Study
_________________________________________________________
% of Women
Adverse Effect
NOLVADEX Placebo
(n=1422)
(n=1437)
_________________________________________________________
Hot Flashes
64
48
Fluid Retention
32
30
Vaginal Discharge
30
15
Nausea
26
24
Irregular Menses
25
19
Weight Loss (>5%)
23
18
Skin Changes
19
15
Increased SGOT
5
3
Increased Bilirubin
2
1
Increased Creatinine
2
1
Thrombocytopenia*
2
1
Thrombotic Events
Deep Vein Thrombosis
0.8
0.2
Pulmonary Embolism
0.5
0.2
Superficial Phlebitis
0.4
0.0
_________________________________________________________
*Defined as a platelet count of <100,000/mm3
In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, NOLVADEX
or placebo was administered for 2 years to women following mastectomy. When compared to
placebo, NOLVADEX showed a significantly higher incidence of hot flashes (19% vs. 8% for
placebo). The incidence of all other adverse reactions was similar in the 2 treatment groups with
the exception of thrombocytopenia where the incidence for NOLVADEX was 10% vs. 3% for
placebo, an observation of borderline statistical significance.
In other adjuvant studies, Toronto and NOLVADEX Adjuvant Trial Organization (NATO),
women received either NOLVADEX or no therapy. In the Toronto study, hot flashes were
observed in 29% of patients for NOLVADEX vs. 1% in the untreated group. In the NATO trial,
hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for
NOLVADEX vs. 0.2% for each in the untreated group.
Ductal Carcinoma in Situ (DCIS): The type and frequency of adverse events in the NSABP B-
24 trial were consistent with those observed in the other adjuvant trials conducted with
NOLVADEX.
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Reduction in Breast Cancer Incidence in High Risk Women: In the NSABP P-1 Trial, there
was an increase in five serious adverse effects in the NOLVADEX group: endometrial cancer
(33 cases in the NOLVADEX group vs. 14 in the placebo group); pulmonary embolism (18
cases in the NOLVADEX group vs. 6 in the placebo group); deep vein thrombosis (30 cases in
the NOLVADEX group vs. 19 in the placebo group); stroke (34 cases in the NOLVADEX group
vs. 24 in the placebo group); cataract formation (540 cases in the NOLVADEX group vs. 483 in
the placebo group) and cataract surgery (101 cases in the NOLVADEX group vs. 63 in the
placebo group) (See WARNINGS and Table 3 in CLINICAL PHARMACOLOGY).
The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only
adverse events more common on NOLVADEX than placebo are shown.
NSABP P-1 Trial: All Adverse Events
% of Women
NOLVADEX
PLACEBO
N=6681
N=6707
Self Reported Symptoms
N=64411
N=64691
Hot Flashes
80
68
Vaginal Discharges
55
35
Vaginal Bleeding
23
22
Laboratory Abnormalities
N=65202
N=65352
Platelets decreased
0.7
0.3
Adverse Effects
N=64923
N=64843
Other Toxicities
Mood
11.6
10.8
Infection/Sepsis
6.0
5.1
Constipation
4.4
3.2
Alopecia
5.2
4.4
Skin
5.6
4.7
Allergy
2.5
2.1
1Number with Quality of Life Questionnaires
2Number with Treatment Follow-up Forms
3Number with Adverse Drug Reaction Forms
In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving NOLVADEX and placebo
therapy, respectively withdrew from the trial for medical reasons. The following are the medical
reasons for withdrawing from NOLVADEX and placebo therapy, respectively: Hot flashes (3.1%
vs. 1.5%) and Vaginal Discharge (0.5% vs. 0.1%).
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In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving NOLVADEX and placebo
therapy, respectively withdrew for non-medical reasons.
On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and
in 80% of women on NOLVADEX. Severe hot flashes occurred in 28% of women on placebo
and 45% of women on NOLVADEX. Vaginal discharge occurred in 35% and 55% of women on
placebo and NOLVADEX respectively; and was severe in 4.5% and 12.3% respectively. There
was no difference in the incidence of vaginal bleeding between treatment arms.
Pediatric Patients - McCune-Albright Syndrome: Mean uterine volume increased after 6
months of treatment and doubled at the end of the one-year study. A causal relationship has not
been established; however, as an increase in the incidence of endometrial adenocarcinoma and
uterine sarcoma has been noted in adults treated with NOLVADEX (see BOXED WARNING),
continued monitoring of McCune-Albright patients treated with NOLVADEX for long-term
effects is recommended. The safety and efficacy of NOLVADEX for girls aged two to 10
years with McCune-Albright Syndrome and precocious puberty have not been studied
beyond one year of treatment. The long-term effects of NOLVADEX therapy in girls have
not been established.
Postmarketing experience: Less frequently reported adverse reactions are vaginal bleeding,
vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been
of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare
reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial
pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been
reported with NOLVADEX therapy. In some of these cases, the time to onset was more than one
year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be
associated with the use of NOLVADEX (see PRECAUTIONS- Drug/Laboratory Testing
Interactions section).
OVERDOSAGE
Signs observed at the highest doses following studies to determine LD50 in animals were
respiratory difficulties and convulsions.
Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer
patients which specifically determined the maximum tolerated dose of NOLVADEX in
evaluating the use of very high doses to reverse multidrug resistance, acute neurotoxicity
manifested by tremor, hyperreflexia, unsteady gait and dizziness were noted. These symptoms
occurred within 3-5 days of beginning NOLVADEX and cleared within 2-5 days after stopping
therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several
days after NOLVADEX was discontinued and neurotoxic symptoms had resolved. The causal
relationship of the seizure to NOLVADEX therapy is unknown. Doses given in these patients
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were all greater than 400 mg/m2 loading dose, followed by maintenance doses of 150 mg/m2 of
NOLVADEX given twice a day.
In the same study, prolongation of the QT interval on the electrocardiogram was noted when
patients were given doses higher than 250 mg/m2 loading dose, followed by maintenance doses
of 80 mg/m2 of NOLVADEX given twice a day. For a woman with a body surface area of 1.5
m2 the minimal loading dose and maintenance doses given at which neurological symptoms and
QT changes occurred were at least 6 fold higher in respect to the maximum recommended dose.
No specific treatment for overdosage is known; treatment must be symptomatic.
DOSAGE AND ADMINISTRATION
For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than
20 mg per day should be given in divided doses (morning and evening).
In three single agent adjuvant studies in women, one 10 mg NOLVADEX tablet was
administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the
NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg
NOLVADEX tablet was given twice a day for at least 5 years. Results of the B-14 study suggest
that continuation of therapy beyond five years does not provide additional benefit (see
CLINICAL PHARMACOLOGY). In the EBCTCG 1995 overview, the reduction in recurrence
and mortality was greater in those studies that used tamoxifen for about 5 years than in those that
used tamoxifen for a shorter period of therapy. There was no indication that doses greater than
20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant
NOLVADEX therapy for patients with breast cancer.
Ductal Carcinoma in Situ (DCIS): The recommended dose is NOLVADEX 20 mg daily for 5
years.
Reduction in Breast Cancer Incidence in High Risk Women: The recommended dose is
NOLVADEX 20 mg daily for 5 years. There are no data to support the use of NOLVADEX other
than for 5 years (See CLINICAL PHARMACOLOGY-Clinical Studies - Reduction in
Breast Cancer Incidence in High Risk Women).
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HOW SUPPLIED
10 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 10 mg of
tamoxifen (round, biconvex, uncoated, white tablet identified with NOLVADEX 600 debossed
on one side and a cameo debossed on the other side) are supplied in bottles of 60 tablets, 180
tablets and 2500 tablets. NDC 0310-0600.
20 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 20 mg of
tamoxifen (round, biconvex, uncoated, white tablet identified with NOLVADEX 604 debossed
on one side and a cameo debossed on the other side) are supplied in bottles of 30 tablets, 90
tablets and 1250 tablets. NDC 0310-0604.
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in a well-closed,
light-resistant container.
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Patient Information about
NOLVADEX
(tamoxifen citrate) Tablets
for Breast Cancer Treatment and Reduction in the Incidence of Breast Cancer
Brand Name: NOLVADEX
(Nol ´va dex)
Generic Name: Tamoxifen (ta-MOX-i-fen)
Please read this information carefully before you begin taking NOLVADEX. It is important to
read this information each time your prescription is filled or refilled in case new information is
available. This summary does not tell you everything about NOLVADEX. Your health care
professional is the best source of information about this medicine. You should talk with him or
her before you begin taking NOLVADEX and at regular checkups. In addition, the professional
package insert contains more detailed information on NOLVADEX.
What are the most important things I should know about NOLVADEX?
NOLVADEX has been shown to help women with advanced breast cancer and in clinical trials of
over 30,000 women with early breast cancer it has been shown to reduce the risk of recurrence.
Also in a trial of 13,000 women at high risk of breast cancer, NOLVADEX reduced the risk of
developing the disease.
Like all medicines, NOLVADEX has some side effects. Most are mild and relate to its hormonal
mode of action. For all women NOLVADEX can, however, also increase the risk of some
serious and potentially life-threatening events, including uterine cancer, blood clots, and
stroke. Some of these events have caused death. NOLVADEX can also increase the risk of
getting cataracts or of needing cataract surgery. If you experience symptoms of any of these, tell
your doctor immediately (see “What should I avoid or do while taking NOLVADEX?”).
If you are a woman at high risk for breast cancer or a woman with DCIS considering
NOLVADEX to reduce your risk of developing breast cancer, you should discuss the
potential benefits versus the potential risks of these serious events with your health care
provider.
What is NOLVADEX?
• NOLVADEX is a prescription medicine used to reduce the risk of getting breast cancer (in
women who have a high risk of getting breast cancer)
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This effect was shown in the Breast Cancer Prevention Trial (BCPT, NSABP P-1), a large study
where over 13,000 women at high risk for breast cancer were to take NOLVADEX or placebo (a
pill without tamoxifen) for 5 years. High risk women were those who were at least 35 years old
and had a combination of risks that made their chances of developing breast cancer greater than
1.67% in the next five years. The risk factors included early age at first menstrual period, late age
at first pregnancy, no pregnancies, close family members with breast cancer (mother, sister, or
daughter), history of previous breast biopsies, or high-risk changes in the breast seen on a biopsy.
Twenty-five percent of the women in the study completed 5 years of treatment, and most women
in this study have been followed for about 4 years. The study showed that NOLVADEX reduced
the chance of getting breast cancer by 44%. The longer-term effects of NOLVADEX on reducing
the chance of getting breast cancer are not known.
We do not know whether taking NOLVADEX for 5 years only delays the appearance of cancer, or
actually decreases the number of tumors that will ever develop since long-term studies have not
been completed.
Some women in this study also experienced serious side effects of NOLVADEX. They are
described in detail in the section, What are the possible side effects of NOLVADEX?. Some of
these women experienced complications related to the treatment of these side effects.
The following table of the major results from the study is intended to be an aid in weighing the
potential benefit of a reduction in risk of breast cancer against the potential risk of serious side
effects of NOLVADEX.
Cases per
Cases per
year out of
year out of
1000 women
1000 women
taking NOLVADEX
taking Placebo
Breast Cancer
3.6
6.5
Endometrial Cancer*
2.3
0.9
Blood clot in the lungs
0.8
0.3
Blood clot in the veins
1.3
0.8
Stroke
1.4
1.0
Cataracts
25.4
22.5
Cataract surgery
46.6
31.4
*In women with a uterus.
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Two European trials of NOLVADEX in women with a high risk of breast cancer were also
conducted. They showed no difference in the number of breast cancer cases between the women
who took tamoxifen and those who got placebo. These studies had trial designs that differed from
that of NSABP P-1 were smaller than P-1, and enrolled women at a lower risk for breast cancer
than those in the P-1 trial.
• In women with DCIS, following breast surgery and radiation, NOLVADEX is indicated to
reduce the risk of invasive breast cancer. The decision regarding therapy with NOLVADEX
for the reduction in breast cancer incidence should be based upon an individual assessment of
the benefits and risks of NOLVADEX therapy.
A trial evaluated the addition of NOLVADEX to lumpectomy and radiation therapy in women
with DCIS. The primary objective was to determine whether 5 years of NOLVADEX therapy
would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral
(the opposite) breast. The incidence of invasive breast cancer was reduced by 43% among women
treated with NOLVADEX.
• NOLVADEX is used to reduce the recurrence of breast cancer in women who have had
surgery and/or radiation therapy to treat early breast cancer. NOLVADEX is also used in
women with breast cancer who are at risk of developing a second breast cancer in the opposite
breast.
The Early Breast Cancer Trialists Collaborative Group reviewed the 10-year results of studies of
NOLVADEX for early breast cancer. Treatment with NOLVADEX for about 5 years reduced the
risk of recurrence of breast cancer and improved overall survival. Treatment with about 5 years of
NOLVADEX also reduced the chance of getting a second breast cancer in the opposite breast by
approximately 50%, a result similar to that seen in the NSABP P-1 study.
• NOLVADEX is used to treat advanced breast cancer in women and men.
Three studies compared NOLVADEX to surgery or radiation to the ovaries in premenopausal
women with advanced breast cancer and found that NOLVADEX was similar to surgery or
radiation in causing tumor shrinkage.
Published studies have demonstrated that NOLVADEX is effective for the treatment of advanced
breast cancer in men.
• NOLVADEX is a prescription tablet available in two dosage strengths: 10 mg tablets and 20
mg tablets. The active ingredient in each tablet is tamoxifen citrate.
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How does NOLVADEX work?
NOLVADEX belongs to a group of medicines called antiestrogens. Antiestrogens work by
blocking the effects of the hormone estrogen in the body. Estrogen may cause the growth of some
types of breast tumors. NOLVADEX may block the growth of tumors that respond to estrogen.
Who should not take NOLVADEX?
• You should not take NOLVADEX to reduce the risk of getting breast cancer if you have ever
had blood clots or if you develop blood clots that require medical treatment. However, if you
are taking NOLVADEX for treatment of early or advanced breast cancer, the benefits of
NOLVADEX may outweigh the risks associated with developing new blood clots. Your
health care professional can assist you in deciding whether NOLVADEX is right for you.
• You should not take NOLVADEX to reduce the risk of getting breast cancer if you are taking
medicines to thin your blood (anticoagulants) like warfarin (Coumadin*).
• You should not take NOLVADEX if you plan to become pregnant while taking NOLVADEX
or during the two months after you stop taking it because NOLVADEX may harm your
unborn child. You should see your doctor immediately and stop taking NOLVADEX if you
become pregnant while taking the drug. Please talk with your doctor about birth control
recommendations. If you are capable of becoming pregnant, you should start NOLVADEX
during a menstrual period or if you have irregular periods have a negative pregnancy test
before beginning to take NOLVADEX. NOLVADEX does not prevent pregnancy, even in
the presence of menstrual irregularity.
• You should not take NOLVADEX if you are breast feeding.
• You should not take NOLVADEX if you have ever had an allergic reaction to NOLVADEX
or tamoxifen citrate (the chemical name) or any of its ingredients.
• NOLVADEX is not known to reduce the risk of breast cancer in women with changes in
breast cancer genes (BRCA1 or BRCA2).
• You should not take NOLVADEX to decrease the chance of getting breast cancer if you are
less than age 35 because NOLVADEX has not been tested in younger women.
• You should not take NOLVADEX to reduce the risk of breast cancer unless you are at high
risk of getting breast cancer. Certain conditions put women at high risk and it is possible to
calculate this risk for any woman. Breast cancer risk assessment tools to help calculate your
risk of breast cancer have been developed and are available to your health care professional.
You should discuss your risks with your health care professional.
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NOLVADEX 08-30-02
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Girls with McCune-Albright Syndrome (a genetic condition associated with premature
puberty) under the age of two and older than 10 years of age should not take NOLVADEX
because treatment in this age group has not been studied. NOLVADEX has not been studied
in boys.
How should I take NOLVADEX?
• Follow your doctor’s instructions about when and how to take NOLVADEX. Read the label
on the container. If you are unsure or have questions, ask your doctor or pharmacist.
• You will take NOLVADEX differently, depending on your diagnosis.
•••• For reduction of the risk of breast cancer, the usual dose is 20 mg a day, for five years.
• For treatment of breast cancer in adult women and men, the usual dose is 20-40 mg a day.
Take the tablets once or twice a day depending on the tablet strength prescribed. If your doctor
has prescribed a different dose, do not change it unless he or she tells you to do so. For
women with early breast cancer, NOLVADEX should be taken for 5 years. For women with
advanced cancer, NOLVADEX should be taken until your doctor feels it is no longer
indicated.
• Take your medicine each day. You may find it easier to remember to take your medicine if
you take it at the same time each day. If you forget to take a dose, take it as soon as you
remember and then take the next dose as usual.
• Swallow the tablets whole with a drink of water.
• You can take NOLVADEX with or without food.
• Do not stop taking your tablets unless your doctor tells you to do so.
Are there other important factors to consider before taking NOLVADEX?
• Tell your doctor if you have ever had blood clots that required medical treatment.
• Because NOLVADEX may affect how other medicines work, always tell your doctor if you
are taking any other prescription or non-prescription (over-the-counter) medications,
particularly if you are taking warfarin to thin your blood.
• You should not become pregnant when taking NOLVADEX or during the two months after
you stop taking it as NOLVADEX may harm your unborn child. Please contact your doctor
for birth control recommendations. NOLVADEX does not prevent pregnancy, even in the
presence of menstrual irregularity. You should see your doctor immediately if you think you
may have become pregnant after starting to take NOLVADEX.
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NOLVADEX 08-30-02
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What should I avoid or do while taking NOLVADEX?
• You should contact your doctor immediately if you notice any of the following symptoms.
Some of these symptoms may suggest that you are experiencing a rare but serious side effect
associated with NOLVADEX (see “What are the possible side effects of NOLVADEX?”).
− new breast lumps
− vaginal bleeding
− changes in your menstrual cycle
− changes in vaginal discharge
− pelvic pain or pressure
− swelling or tenderness in your calf
− unexplained breathlessness (shortness of breath)
− sudden chest pain
− coughing up blood
− changes in your vision
If you see a health care professional who is new to you (an emergency room doctor, another
doctor in the practice), tell him or her that you take NOLVADEX or have previously taken
NOLVADEX.
• Because NOLVADEX may affect how other medicines work, always tell your doctor if you
are taking any other prescription or non-prescription (over-the-counter) medicines. Be sure to
tell your doctor if you are taking warfarin (Coumadin) to thin your blood.
• You should not become pregnant when taking NOLVADEX or during the two months after
you stop taking it because NOLVADEX may harm your unborn child. You should see your
doctor immediately if you think you may have become pregnant after starting to take
NOLVADEX. Please talk with your doctor about birth control recommendations. If you are
taking NOLVADEX to reduce your risk of getting breast cancer, and you are sexually active,
NOLVADEX should be started during your menstrual period. If you have irregular periods,
you should have a negative pregnancy test before you start NOLVADEX. NOLVADEX does
not prevent pregnancy, even in the presence of menstrual irregularity.
• If you are taking NOLVADEX to reduce your risk of getting breast cancer, you should know
that NOLVADEX does not prevent all breast cancers. While you are taking NOLVADEX and
after you stop taking NOLVADEX and in keeping with your doctor’s recommendation, you
should have annual gynecological check-ups which should include breast exams and
mammograms. If breast cancer occurs, there is no guarantee that it will be detected at an early
stage. This is why it is important to continue with regular check-ups.
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What are the possible side effects of NOLVADEX?
Like many medicines, NOLVADEX causes side effects in most patients. The majority of the side
effects seen with NOLVADEX have been mild and do not usually cause breast cancer patients to
stop taking the medication. In women with breast cancer, withdrawal from NOLVADEX therapy is
about 5%. Approximately 15% of women who took NOLVADEX to reduce the chance of getting
breast cancer stopped treatment because of side effects.
The most common side effects reported with NOLVADEX are: hot flashes; vaginal discharge or
bleeding; and menstrual irregularities (these side effects may be mild or may be a sign of a more
serious side effect). Women may experience hair loss, skin rashes (itching or peeling skin) or
headaches; or inflammation of the lungs, which may have the same symptoms as pneumonia, such
as breathlessness and cough; however, hair loss is uncommon and is usually mild..
A rare but serious side effect of NOLVADEX is a blood clot in the veins. Blood clots stop the
flow of blood and can cause serious medical problems, disability, or death. Women who take
NOLVADEX are at increased risk for developing blood clots in the lungs and legs. Some women
may develop more than one blood clot, even if NOLVADEX is stopped. Women may also have
complications from treating the clot, such as bleeding from thinning the blood too much.
Symptoms of a blood clot in the lungs may include sudden chest pain, shortness of breath or
coughing up blood. Symptoms of a blood clot in the legs are pain or swelling in the calves. A
blood clot in the legs may move to the lungs. If you experience any of these symptoms of a blood
clot, contact your doctor immediately.
NOLVADEX increases the chance of having a stroke, which can cause serious medical problems,
disability, or death. If you experience any symptoms of stroke, such as weakness, difficulty
walking or talking, or numbness, contact your doctor immediately.
NOLVADEX increases the chance of changes occurring in the lining (endometrium) or body of
your uterus which can be serious and could include cancer. If you have not had a hysterectomy
(removal of the uterus), it is important for you to contact your doctor immediately if you
experience any unusual vaginal discharge, vaginal bleeding, or menstrual irregularities; or pain or
pressure in the pelvis (lower stomach). These may be caused by changes to the lining
(endometrium) or body of your uterus. It is important to bring them to your doctor’s attention
without delay as they can occasionally indicate the start of something more serious and even life-
threatening.
NOLVADEX may cause cataracts or changes to parts of the eye known as the cornea or retina.
NOLVADEX can increase the chance of needing cataract surgery, and can cause blood clots in
the veins of the eye. NOLVADEX can result in difficulty in distinguishing different colors. If you
experience any changes in your vision, tell your doctor immediately.
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NOLVADEX 08-30-02
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Rare side effects, which may be serious, include certain liver problems such as jaundice (which
may be seen as yellowing of the whites of the eyes) or hypertriglyceridemia (increased levels of
fats in the blood) sometimes with pancreatitis (pain or tenderness in the upper abdomen). Stop
taking NOLVADEX and contact your doctor immediately if you develop angioedema (swelling of
the face, lips, tongue and/or throat) even if you have been taking NOLVADEX for a long time.
If you are a woman receiving NOLVADEX for treatment of advanced breast cancer, and you
experience excessive nausea, vomiting or thirst, tell your doctor immediately. This may mean that
there are changes in the amount of calcium in your blood (hypercalcemia). Your doctor will
evaluate this.
In patients with breast cancer, a temporary increase in the size of the tumor may occur and
sometimes results in muscle aches/bone pain and skin redness. This condition may occur shortly
after starting NOLVADEX and may be associated with a good response to treatment.
Many of these side effects happen only rarely. However, you should contact your doctor if you
think you have any of these or any other problems with your NOLVADEX. Some side effects of
NOLVADEX may become apparent soon after starting the drug, but others may first appear at any
time during therapy.
This summary does not include all possible side effects with NOLVADEX. It is important to talk
to your health care professional about possible side effects. If you want to read more, ask your
doctor or pharmacist to give you the professional labeling.
How should I store NOLVADEX?
NOLVADEX Tablets should be stored at room temperature (68-77°F). Keep in a well-closed,
light-resistant container. Keep out of the reach of children.
Do not take your tablets after the expiration date on the container. Be sure that any discarded
tablets are out of the reach of children.
This leaflet provides you with a summary of information about NOLVADEX. Medicines are
sometimes prescribed for uses other than those listed. NOLVADEX has been prescribed
specifically for you by your doctor. Do not give your medicine to anyone else, even if they have a
similar condition, because it may harm them.
If you have any questions or concerns, contact your doctor or pharmacist. Your pharmacist also
has a longer leaflet about NOLVADEX written for health care professionals that you can ask to
read. For more information about NOLVADEX or breast cancer, call 1-800-34 LIFE 4.
*Coumadin is a registered trademark of Bristol-Myers Squibb Pharmaceuticals.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NOLVADEX 08-30-02
Page 42
AstraZeneca Pharmaceuticals LP
Wilmington, Delaware 19850-5437
Rev 08-30-02 08-01-02 SIC XXXXX-XX
Printed in USA 2002 AstraZeneca Group of Companies
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
David Orloff
8/30/02 02:10:26 PM
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21109lbl,17970s50lbl.pdf', 'application_number': 17970, 'submission_type': 'SUPPL ', 'submission_number': 50}
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EL:L50
PRESCRIBING INFORMATION
ESKALITH
(lithium carbonate)
Capsules, 300 mg
ESKALITH CR
(lithium carbonate)
Controlled-Release
Tablets, 450 mg
WARNING
Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to
therapeutic levels. Facilities for prompt and accurate serum lithium determinations should be
available before initiating therapy (see DOSAGE AND ADMINISTRATION).
DESCRIPTION
ESKALITH contains lithium carbonate, a white, light alkaline powder with molecular formula
Li2CO3 and molecular weight 73.89. Lithium is an element of the alkali-metal group with atomic
number 3, atomic weight 6.94 and an emission line at 671 nm on the flame photometer.
ESKALITH Capsules: Each capsule, with opaque gray cap and opaque yellow body, is
imprinted with the product name ESKALITH and SB and contains lithium carbonate, 300 mg.
Inactive ingredients consist of benzyl alcohol, cetylpyridinium chloride, D&C Yellow No. 10,
FD&C Green No. 3, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, lactose, magnesium
stearate, povidone, sodium lauryl sulfate, titanium dioxide, and trace amounts of other inactive
ingredients.
ESKALITH CR Controlled-Release Tablets: Each round, yellow, biconvex tablet,
debossed with SKF and J10 on one side and scored on the other side, contains lithium carbonate,
450 mg. Inactive ingredients consist of alginic acid, gelatin, iron oxide, magnesium stearate, and
sodium starch glycolate.
ESKALITH CR Tablets 450 mg are designed to release a portion of the dose initially and the
remainder gradually; the release pattern of the controlled release tablets reduces the variability in
lithium blood levels seen with the immediate release dosage forms.
ACTIONS
Preclinical studies have shown that lithium alters sodium transport in nerve and muscle cells
and effects a shift toward intraneuronal metabolism of catecholamines, but the specific
biochemical mechanism of lithium action in mania is unknown.
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2
INDICATIONS
ESKALITH (lithium carbonate) is indicated in the treatment of manic episodes of manic-
depressive illness. Maintenance therapy prevents or diminishes the intensity of subsequent
episodes in those manic-depressive patients with a history of mania.
Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for
sleep, flight of ideas, grandiosity, elation, poor judgment, aggressiveness and possibly hostility.
When given to a patient experiencing a manic episode, ESKALITH may produce a normalization
of symptomatology within 1 to 3 weeks.
WARNINGS
Lithium should generally not be given to patients with significant renal or cardiovascular
disease, severe debilitation or dehydration, or sodium depletion, since the risk of lithium toxicity
is very high in such patients. If the psychiatric indication is life-threatening, and if such a patient
fails to respond to other measures, lithium treatment may be undertaken with extreme caution,
including daily serum lithium determinations and adjustment to the usually low doses ordinarily
tolerated by these individuals. In such instances, hospitalization is a necessity.
Chronic lithium therapy may be associated with diminution of renal concentrating ability,
occasionally presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia. Such
patients should be carefully managed to avoid dehydration with resulting lithium retention and
toxicity. This condition is usually reversible when lithium is discontinued.
Morphologic changes with glomerular and interstitial fibrosis and nephron atrophy have been
reported in patients on chronic lithium therapy. Morphologic changes have also been seen in
manic-depressive patients never exposed to lithium. The relationship between renal functional
and morphologic changes and their association with lithium therapy have not been established.
When kidney function is assessed, for baseline data prior to starting lithium therapy or
thereafter, routine urinalysis and other tests may be used to evaluate tubular function (e.g., urine
specific gravity or osmolality following a period of water deprivation, or 24-hour urine volume)
and glomerular function (e.g., serum creatinine or creatinine clearance). During lithium therapy,
progressive or sudden changes in renal function, even within the normal range, indicate the need
for reevaluation of treatment.
An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and
confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN and FBS) has
occurred in a few patients treated with lithium plus a neuroleptic. In some instances, the
syndrome was followed by irreversible brain damage. Because of a possible causal relationship
between these events and the concomitant administration of lithium and neuroleptics, patients
receiving such combined therapy should be monitored closely for early evidence of neurologic
toxicity and treatment discontinued promptly if such signs appear. This encephalopathic
syndrome may be similar to or the same as neuroleptic malignant syndrome (NMS).
Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to
therapeutic levels (see DOSAGE AND ADMINISTRATION).
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3
Outpatients and their families should be warned that the patient must discontinue lithium
carbonate therapy and contact his physician if such clinical signs of lithium toxicity as diarrhea,
vomiting, tremor, mild ataxia, drowsiness, or muscular weakness occur.
Lithium carbonate may impair mental and/or physical abilities. Caution patients about
activities requiring alertness (e.g., operating vehicles or machinery).
Lithium may prolong the effects of neuromuscular blocking agents. Therefore, neuromuscular
blocking agents should be given with caution to patients receiving lithium.
Usage in Pregnancy: Adverse effects on implantation in rats, embryo viability in mice and
metabolism in vitro of rat testes and human spermatozoa have been attributed to lithium, as have
teratogenicity in submammalian species and cleft palates in mice.
In humans, lithium carbonate may cause fetal harm when administered to a pregnant woman.
Data from lithium birth registries suggest an increase in cardiac and other anomalies, especially
Ebstein’s anomaly. If this drug is used in women of childbearing potential, or during pregnancy,
or if a patient becomes pregnant while taking this drug, the patient should be apprised of the
potential hazard to the fetus.
Usage in Nursing Mothers: Lithium is excreted in human milk. Nursing should not be
undertaken during lithium therapy except in rare and unusual circumstances where, in the view
of the physician, the potential benefits to the mother outweigh possible hazards to the child.
Usage in Pediatric Patients: Since information regarding the safety and effectiveness of
lithium carbonate in children under 12 years of age is not available, its use in such patients is not
recommended.
There has been a report of a transient syndrome of acute dystonia and hyperreflexia occurring
in a 15 kg child who ingested 300 mg of lithium carbonate.
Usage in the Elderly: Elderly patients often require lower lithium dosages to achieve
therapeutic serum levels. They may also exhibit adverse reactions at serum levels ordinarily
tolerated by younger patients.
PRECAUTIONS
General: The ability to tolerate lithium is greater during the acute manic phase and decreases
when manic symptoms subside (see DOSAGE AND ADMINISTRATION).
The distribution space of lithium approximates that of total body water. Lithium is primarily
excreted in urine with insignificant excretion in feces. Renal excretion of lithium is proportional
to its plasma concentration. The half-life of elimination of lithium is approximately 24 hours.
Lithium decreases sodium reabsorption by the renal tubules which could lead to sodium
depletion. Therefore, it is essential for the patient to maintain a normal diet, including salt, and
an adequate fluid intake (2,500 to 3,000 mL) at least during the initial stabilization period.
Decreased tolerance to lithium has been reported to ensue from protracted sweating or diarrhea
and, if such occur, supplemental fluid and salt should be administered under careful medical
supervision and lithium intake reduced or suspended until the condition is resolved.
In addition to sweating and diarrhea, concomitant infection with elevated temperatures may
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
also necessitate a temporary reduction or cessation of medication.
Previously existing underlying thyroid disorders do not necessarily constitute a
contraindication to lithium treatment; where hypothyroidism exists, careful monitoring of thyroid
function during lithium stabilization and maintenance allows for correction of changing thyroid
parameters, if any; where hypothyroidism occurs during lithium stabilization and maintenance,
supplemental thyroid treatment may be used.
Drug Interactions: Caution should be used when lithium and diuretics are used concomitantly
because diuretic-induced sodium loss may reduce the renal clearance of lithium and increase
serum lithium levels with risk of lithium toxicity. Patients receiving such combined therapy
should have serum lithium levels monitored closely and the lithium dosage adjusted if necessary.
Lithium levels should be closely monitored when patients initiate or discontinue NSAID use.
In some cases, lithium toxicity has resulted from interactions between an NSAID and lithium.
Indomethacin and piroxicam have been reported to increase significantly steady-state plasma
lithium concentrations. There is also evidence that other nonsteroidal anti-inflammatory agents,
including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect. In a study
conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately
17% in subjects receiving lithium 450 mg b.i.d. with celecoxib 200 mg b.i.d. as compared to
subjects receiving lithium alone.
Concurrent use of metronidazole with lithium may provoke lithium toxicity due to reduced
renal clearance. Patients receiving such combined therapy should be monitored closely.
There is evidence that angiotensin-converting enzyme inhibitors, such as enalapril and
captopril, and angiotension II receptor antagonists, such as losartan, may substantially increase
steady-state plasma lithium levels, sometimes resulting in lithium toxicity. When such
combinations are used, lithium dosage may need to be decreased, and plasma lithium levels
should be measured more often.
Concurrent use of calcium channel blocking agents with lithium may increase the risk of
neurotoxicity in the form of ataxia, tremors, nausea, vomiting, diarrhea, and/or tinnitus. Caution
is recommended.
The concomitant administration of lithium with selective serotonin reuptake inhibitors should
be undertaken with caution as this combination has been reported to result in symptoms such as
diarrhea, confusion, tremor, dizziness, and agitation.
The following drugs can lower serum lithium concentrations by increasing urinary lithium
excretion: acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium
bicarbonate.
The following have also been shown to interact with lithium: methyldopa, phenytoin, and
carbamazepine.
ADVERSE REACTIONS
The occurrence and severity of adverse reactions are generally directly related to serum
lithium concentrations as well as to individual patient sensitivity to lithium, and generally occur
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5
more frequently and with greater severity at higher concentrations.
Adverse reactions may be encountered at serum lithium levels below 1.5 mEq/L. Mild to
moderate adverse reactions may occur at levels from 1.5 to 2.5 mEq/L, and moderate to severe
reactions may be seen at levels of 2.0 mEq/L and above.
Fine hand tremor, polyuria, and mild thirst may occur during initial therapy for the acute
manic phase, and may persist throughout treatment. Transient and mild nausea and general
discomfort may also appear during the first few days of lithium administration.
These side effects usually subside with continued treatment or a temporary reduction or
cessation of dosage. If persistent, cessation of lithium therapy may be required.
Diarrhea, vomiting, drowsiness, muscular weakness, and lack of coordination may be early
signs of lithium intoxication, and can occur at lithium levels below 2.0 mEq/L. At higher levels,
ataxia, giddiness, tinnitus, blurred vision, and a large output of dilute urine may be seen. Serum
lithium levels above 3.0 mEq/L may produce a complex clinical picture, involving multiple
organs and organ systems. Serum lithium levels should not be permitted to exceed 2.0 mEq/L
during the acute treatment phase.
The following reactions have been reported and appear to be related to serum lithium levels,
including levels within the therapeutic range:
Neuromuscular/Central Nervous System: Tremor, muscle hyperirritability (fasciculations,
twitching, clonic movements of whole limbs), hypertonicity, ataxia, choreo-athetotic movements,
hyperactive deep tendon reflex, extrapyramidal symptoms including acute dystonia, cogwheel
rigidity, blackout spells, epileptiform seizures, slurred speech, dizziness, vertigo, downbeat
nystagmus, incontinence of urine or feces, somnolence, psychomotor retardation, restlessness,
confusion, stupor, coma, tongue movements, tics, tinnitus, hallucinations, poor memory, slowed
intellectual functioning, startled response, worsening of organic brain syndromes, myasthenia
gravis (rarely).
Cardiovascular: Cardiac arrhythmia, hypotension, peripheral circulatory collapse,
bradycardia, sinus node dysfunction with severe bradycardia (which may result in syncope).
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, gastritis, salivary gland swelling,
abdominal pain, excessive salivation, flatulence, indigestion.
Genitourinary: Glycosuria, decreased creatinine clearance, albuminuria, oliguria, and
symptoms of nephrogenic diabetes insipidus including polyuria, thirst and polydipsia.
Dermatologic: Drying and thinning of hair, alopecia, anesthesia of skin, acne, chronic
folliculitis, xerosis cutis, psoriasis or its exacerbation, generalized pruritus with or without rash,
cutaneous ulcers, angioedema.
Autonomic: Blurred vision, dry mouth, impotence/sexual dysfunction.
Thyroid Abnormalities: Euthyroid goiter and/or hypothyroidism (including myxedema)
accompanied by lower T3 and T4. I131 uptake may be elevated. (See PRECAUTIONS.)
Paradoxically, rare cases of hyperthyroidism have been reported.
EEG Changes: Diffuse slowing, widening of the frequency spectrum, potentiation and
disorganization of background rhythm.
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6
EKG Changes: Reversible flattening, isoelectricity or inversion of T-waves.
Miscellaneous: Fatigue, lethargy, transient scotomata, exophthalmos, dehydration, weight
loss, leukocytosis, headache, transient hyperglycemia, hypercalcemia, hyperparathyroidism,
excessive weight gain, edematous swelling of ankles or wrists, metallic taste, dysgeusia/taste
distortion, salty taste, thirst, swollen lips, tightness in chest, swollen and/or painful joints, fever,
polyarthralgia, dental caries.
Some reports of nephrogenic diabetes insipidus, hyperparathyroidism, and hypothyroidism
which persist after lithium discontinuation have been received.
A few reports have been received of the development of painful discoloration of fingers and
toes and coldness of the extremities within one day of the starting of treatment with lithium. The
mechanism through which these symptoms (resembling Raynaud’s syndrome) developed is not
known. Recovery followed discontinuance.
Cases of pseudotumor cerebri (increased intracranial pressure and papilledema) have been
reported with lithium use. If undetected, this condition may result in enlargement of the blind
spot, constriction of visual fields, and eventual blindness due to optic atrophy. Lithium should be
discontinued, if clinically possible, if this syndrome occurs.
DOSAGE AND ADMINISTRATION
Immediate-release capsules are usually given t.i.d. or q.i.d. Doses of controlled-release tablets
are usually given b.i.d. (approximately 12-hour intervals). When initiating therapy with
immediate-release or controlled-release lithium, dosage must be individualized according to
serum levels and clinical response.
When switching a patient from immediate-release capsules to ESKALITH CR Controlled-
Release Tablets, give the same total daily dose when possible. Most patients on maintenance
therapy are stabilized on 900 mg daily, e.g., ESKALITH CR 450 mg b.i.d. When the previous
dosage of immediate-release lithium is not a multiple of 450 mg, e.g., 1,500 mg, initiate
ESKALITH CR at the multiple of 450 mg nearest to, but below, the original daily dose, i.e.,
1,350 mg. When the 2 doses are unequal, give the larger dose in the evening. In the above
example, with a total daily dose of 1,350 mg, generally 450 mg of ESKALITH CR should be
given in the morning and 900 mg of ESKALITH CR in the evening. If desired, the total daily
dose of 1,350 mg can be given in 3 equal 450-mg doses of ESKALITH CR. These patients
should be monitored at 1- to 2-week intervals, and dosage adjusted if necessary, until stable and
satisfactory serum levels and clinical state are achieved.
When patients require closer titration than that available with doses of ESKALITH CR in
increments of 450 mg, immediate-release capsules should be used.
Acute Mania: Optimal patient response to ESKALITH can usually be established and
maintained with 1,800 mg per day in divided doses. Such doses will normally produce the
desired serum lithium level ranging between 1.0 and 1.5 mEq/L.
Dosage must be individualized according to serum levels and clinical response. Regular
monitoring of the patient’s clinical state and serum lithium levels is necessary. Serum levels
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
should be determined twice per week during the acute phase, and until the serum level and
clinical condition of the patient have been stabilized.
Long-Term Control: The desirable serum lithium levels are 0.6 to 1.2 mEq/L. Dosage will
vary from one individual to another, but usually 900 mg to 1,200 mg per day in divided doses
will maintain this level. Serum lithium levels in uncomplicated cases receiving maintenance
therapy during remission should be monitored at least every two months.
Patients unusually sensitive to lithium may exhibit toxic signs at serum levels below
1.0 mEq/L.
N.B.: Blood samples for serum lithium determinations should be drawn immediately prior to the
next dose when lithium concentrations are relatively stable (i.e., 8 to 12 hours after the previous
dose). Total reliance must not be placed on serum levels alone. Accurate patient evaluation
requires both clinical and laboratory analysis.
Elderly patients often respond to reduced dosage, and may exhibit signs of toxicity at serum
levels ordinarily tolerated by younger patients.
OVERDOSAGE
The toxic levels for lithium are close to the therapeutic levels. It is therefore important that
patients and their families be cautioned to watch for early toxic symptoms and to discontinue the
drug and inform the physician should they occur. Toxic symptoms are listed in detail under
ADVERSE REACTIONS.
Treatment: No specific antidote for lithium poisoning is known. Early symptoms of
lithium toxicity can usually be treated by reduction or cessation of dosage of the drug and
resumption of the treatment at a lower dose after 24 to 48 hours. In severe cases of lithium
poisoning, the first and foremost goal of treatment consists of elimination of this ion from
the patient. Treatment is essentially the same as that used in barbiturate poisoning: 1)
gastric lavage, 2) correction of fluid and electrolyte imbalance, and 3) regulation of kidney
function. Urea, mannitol and aminophylline all produce significant increases in lithium
excretion. Hemodialysis is an effective and rapid means of removing the ion from the
severely toxic patient. Infection prophylaxis, regular chest X-rays and preservation of
adequate respiration are essential.
HOW SUPPLIED
ESKALITH Capsules 300 mg are gray and yellow capsules imprinted with “ESKALITH” and
“SB” on one side of each half of the capsule, in bottles of 100 (NDC 0007-4007-20).
ESKALITH CR Tablets 450 mg are round, yellow, biconvex, controlled-release tablets,
debossed with “SKF” and “J10” on one side and scored on the other side, in bottles of 100 (NDC
0007-4010-20).
STORAGE CONDITIONS: Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F)
[see USP Controlled Room Temperature].
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For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Manufactured by
Cardinal Health
Winchester, KY 40391 for
GlaxoSmithKline
Research Triangle Park, NC 27709
©2003, GlaxoSmithKline. All rights reserved.
September 2003
EL:L50
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/16860slr074,18152slr020_eskalith_lbl.pdf', 'application_number': 17971, 'submission_type': 'SUPPL ', 'submission_number': 20}
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Hemabate®
carboprost tromethamine
injection, USP
DESCRIPTION
HEMABATE Sterile Solution, an oxytocic, contains the tromethamine salt of the (15S)
15 methyl analogue of naturally occurring prostaglandin F2α in a solution suitable for
intramuscular injection.
Carboprost tromethamine is the established name for the active ingredient in
HEMABATE. Four other chemical names are:
1. (15S)-15-methyl prostaglandin F2α tromethamine salt
2. 7-(3α,5α-dihydroxy-2ß-[(3S)-3-hydroxy-3-methyl-trans-1-octenyl]-1α
cyclopentyl]-cis-5-heptenoic acid compound with 2-amino-2-(hydroxymethyl)
1,3-propanediol
3. (15S)-9α,11α,15-trihydroxy-15-methylprosta-cis-5, trans-13-dienoic acid
tromethamine salt
4. (15S)-15-methyl PGF2α-THAM
The structural formula is represented below: structural formula
The molecular formula is C25H47O8N. The molecular weight of carboprost tromethamine
is 489.64. It is a white to slightly off-white crystalline powder. It generally melts between
95° and 105° C, depending on the rate of heating.
Carboprost tromethamine dissolves readily in water at room temperature at a
concentration greater than 75 mg/mL.
Each mL of HEMABATE Sterile Solution contains carboprost tromethamine equivalent
to 250 mcg of carboprost, 83 mcg tromethamine, 9 mg sodium chloride, and 9.45 mg
benzyl alcohol added as preservative. When necessary, pH is adjusted with sodium
hydroxide and/or hydrochloric acid. The solution is sterile.
CLINICAL PHARMACOLOGY
Carboprost tromethamine administered intramuscularly stimulates in the gravid uterus
myometrial contractions similar to labor contractions at the end of a full term pregnancy.
Whether or not these contractions result from a direct effect of carboprost on the
1
Reference ID: 3420404
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myometrium has not been determined. Nonetheless, they evacuate the products of
conception from the uterus in most cases.
Postpartum, the resultant myometrial contractions provide hemostasis at the site of
placentation.
Carboprost tromethamine also stimulates the smooth muscle of the human
gastrointestinal tract. This activity may produce the vomiting or diarrhea or both that is
common when carboprost tromethamine is used to terminate pregnancy and for use
postpartum. In laboratory animals and also in humans carboprost tromethamine can
elevate body temperature. With the clinical doses of carboprost tromethamine used for
the termination of pregnancy, and for use postpartum, some patients do experience
transient temperature increases.
In laboratory animals and in humans large doses of carboprost tromethamine can raise
blood pressure, probably by contracting the vascular smooth muscle. With the doses of
carboprost tromethamine used for terminating pregnancy, this effect has not been
clinically significant. In laboratory animals and also in humans carboprost tromethamine
can elevate body temperature. With the clinical doses of carboprost tromethamine used
for the termination of pregnancy, some patients do experience temperature increases. In
some patients, carboprost tromethamine may cause transient bronchoconstriction.
Drug plasma concentrations were determined by radioimmunoassay in peripheral blood
samples collected by different investigators from 10 patients undergoing abortion. The
patients had been injected intramuscularly with 250 micrograms of carboprost at two
hour intervals. Blood levels of drug peaked at an average of 2060 picograms/mL one-half
hour after the first injection then declined to an average concentration of 770
picograms/mL two hours after the first injection just before the second injection. The
average plasma concentration one-half hour after the second injection was slightly higher
(2663 picograms/mL) than that after the first injection and decreased again to an average
of 1047 picograms/mL by two hours after the second injection. Plasma samples were
collected from 5 of these 10 patients following additional injections of the prostaglandin.
The average peak concentrations of drug were slightly higher following each successive
injection of the prostaglandin, but always decreased to levels less than the preceding peak
values by two hours after each injection.
Five women who had delivery spontaneously at term were treated immediately
postpartum with a single injection of 250 micrograms of carboprost tromethamine.
Peripheral blood samples were collected at several times during the four hours following
treatment and carboprost tromethamine levels were determined by radioimmunoassay.
The highest concentration of carboprost tromethamine was observed at 15 minutes in two
patients (3009 and 2916 picograms/mL), at 30 minutes in two patients (3097 and 2792
picograms/mL), and at 60 minutes in one patient (2718 picograms/mL).
INDICATIONS AND USAGE
2
Reference ID: 3420404
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HEMABATE Sterile Solution is indicated for aborting pregnancy between the 13th and
20th weeks of gestation as calculated from the first day of the last normal menstrual
period and in the following conditions related to second trimester abortion:
1. Failure of expulsion of the fetus during the course of treatment by another
method;
2. Premature rupture of membranes in intrauterine methods with loss of drug and
insufficient or absent uterine activity;
3. Requirement of a repeat intrauterine instillation of drug for expulsion of the fetus;
4. Inadvertent or spontaneous rupture of membranes in the presence of a previable
fetus and absence of adequate activity for expulsion.
HEMABATE is indicated for the treatment of postpartum hemorrhage due to uterine
atony which has not responded to conventional methods of management. Prior treatment
should include the use of intravenously administered oxytocin, manipulative techniques
such as uterine massage and, unless contraindicated, intramuscular ergot preparations.
Studies have shown that in such cases, the use of HEMABATE has resulted in
satisfactory control of hemorrhage, although it is unclear whether or not ongoing or
delayed effects of previously administered ecbolic agents have contributed to the
outcome. In a high proportion of cases, HEMABATE used in this manner has resulted in
the cessation of life threatening bleeding and the avoidance of emergency surgical
intervention.
CONTRAINDICATIONS
1. Hypersensitivity (including anaphylaxis and angioedema) to HEMABATE Sterile
Solution [see ADVERSE REACTIONS, Post-marketing Experience]
2. Acute pelvic inflammatory disease
3. Patients with active cardiac, pulmonary, renal or hepatic disease
WARNINGS
HEMABATE Sterile Solution (carboprost tromethamine), like other potent oxytocic
agents, should be used only with strict adherence to recommended dosages.
HEMABATE should be used by medically trained personnel in a hospital which can
provide immediate intensive care and acute surgical facilities.
HEMABATE does not appear to directly affect the fetoplacental unit. Therefore, the
possibility does exist that the previable fetus aborted by HEMABATE could exhibit
transient life signs. HEMABATE is not indicated if the fetus in utero has reached the
stage of viability. HEMABATE should not be considered a feticidal agent.
Evidence from animal studies has suggested that certain other prostaglandins have some
teratogenic potential. Although these studies do not indicate that HEMABATE is
3
Reference ID: 3420404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
teratogenic, any pregnancy termination with HEMABATE that fails should be completed
by some other means.
This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated
with a fatal "Gasping Syndrome" in premature infants.
PRECAUTIONS
General
Animal studies lasting several weeks at high doses have shown that prostaglandins of the
E and F series can induce proliferation of bone. Such effects have also been noted in
newborn infants who have received prostaglandin E1 during prolonged treatment. There
is no evidence that short term administration of HEMABATE Sterile Solution can cause
similar bone effects.
In patients with a history of asthma, hypo- or hypertension, cardiovascular, renal, or
hepatic disease, anemia, jaundice, diabetes, or epilepsy, HEMABATE should be used
cautiously.
As with any oxytocic agent, HEMABATE should be used with caution in patients with
compromised (scarred) uteri.
Abortion
As with spontaneous abortion, a process which is sometimes incomplete, abortion
induced by HEMABATE may be expected to be incomplete in about 20% of cases.
Although the incidence of cervical trauma is extremely small, the cervix should always
be carefully examined immediately post-abortion.
Use of HEMABATE is associated with transient pyrexia that may be due to its effect on
hypothalamic thermoregulation. Temperature elevations exceeding 2° F (1.1° C) were
observed in approximately one-eighth of the patients who received the recommended
dosage regimen. In all cases, temperature returned to normal when therapy ended.
Differentiation of post-abortion endometritis from drug-induced temperature elevations is
difficult, but with increasing clinical experience, the distinctions become more obvious
and are summarized below:
Endometritis
Pyrexia induced by
pyrexia
HEMABATE
1. Time of onset: Typically, on third post-
Within 1 to 16 hours after the first
abortional day (38° C or higher).
injection.
2. Duration: Untreated pyrexia and
Temperatures revert to pretreatment
infection continue and may give rise to
levels after discontinuation of therapy
other pelvic infections.
without any other treatment.
3. Retention: Products of conception are
Temperature elevation occurs whether or
often retained in the cervical os or
not tissue is retained.
uterine cavity.
4
Reference ID: 3420404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. Histology: Endometrium is infiltrated
Although the endometrial stroma may be
with lymphocytes and some areas are
edematous and vascular, it is not
necrotic and hemorrhagic.
inflamed.
5. The uterus: Often remains boggy and
Uterine involution normal and uterus is
soft with tenderness over the fundus,
not tender.
and pain on moving the cervix on
bimanual examination.
6. Discharge: Often associated with foul-
Lochia normal.
smelling lochia and leukorrhea.
7. Cervical culture: The culture of pathological organisms from the cervix or uterine
cavity after abortion alone does not warrant the diagnosis of septic abortion in the
absence of clinical evidence of sepsis. Pathogens have been cultured soon after
abortion in patients with no infections. Persistent positive culture with clear clinical
signs of infections are significant in the differential diagnosis.
8. Blood count: Leukocytosis and differential white cell counts do not distinguish
between endometritis and hyperthermia caused by HEMABATE since total WBC’s
may increase during infection and transient leukocytosis may also be drug-induced.
Fluids should be forced in patients with drug-induced fever and no clinical or
bacteriological evidence of intrauterine infection. Any other simple empirical
measures for temperature reduction are unnecessary because all fevers induced by
HEMABATE have been transient or self-limiting.
Postpartum Hemorrhage
Increased blood pressure. In the postpartum hemorrhage series, 5/115 (4%) of patients
had an increase of blood pressure reported as a side effect. The degree of hypertension
was moderate and it is not certain as to whether this was in fact due to a direct effect of
HEMABATE or a return to a status of pregnancy associated hypertension manifest by the
correction of hypovolemic shock. In any event the cases reported did not require specific
therapy for the elevated blood pressure.
Use in patients with chorioamnionitis. During the clinical trials with HEMABATE,
chorioamnionitis was identified as a complication contributing to postpartum uterine
atony and hemorrhage in 8/115 (7%) of cases, 3 of which failed to respond to
HEMABATE. This complication during labor may have an inhibitory effect on the
uterine response to HEMABATE similar to what has been reported for other oxytocic
agents.1
Drug Interactions
HEMABATE may augment the activity of other oxytocic agents. Concomitant use with
other oxytocic agents is not recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenic bioassay studies have not been conducted in animals with HEMABATE
due to the limited indications for use and short duration of administration. No evidence of
mutagenicity was observed in the Micronucleus Test or Ames Assay.
5
Reference ID: 3420404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy: Teratogenic Effects: Pregnancy Category C
Animal studies do not indicate that HEMABATE is teratogenic, however, it has been
shown to be embryotoxic in rats and rabbits and any dose which produces increased
uterine tone could put the embryo or fetus at risk.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
The adverse effects of HEMABATE Sterile Solution are generally transient and
reversible when therapy ends. The most frequent adverse reactions observed are related
to its contractile effect on smooth muscle.
In patients studied, approximately two-thirds experienced vomiting and diarrhea,
approximately one-third had nausea, one-eighth had a temperature increase greater than
2° F, and one-fourteenth experienced flushing.
The pretreatment or concurrent administration of antiemetic and antidiarrheal drugs
decreases considerably the very high incidence of gastrointestinal effects common with
all prostaglandins used for abortion. Their use should be considered an integral part of the
management of patients undergoing abortion with HEMABATE.
Of those patients experiencing a temperature elevation, approximately one-sixteenth had
a clinical diagnosis of endometritis. The remaining temperature elevations returned to
normal within several hours after the last injection.
Adverse effects observed during the use of HEMABATE for abortion and for
hemorrhage, not all of which are clearly drug related, in decreasing order of frequency
include:
Vomiting
Nervousness
Diarrhea
Nosebleed
Nausea
Sleep disorders
Flushing or hot flashes
Dyspnea
Chills or shivering
Tightness in chest
Coughing
Wheezing
Headaches
Posterior cervical
Endometritis
perforation
Hiccough
Weakness
Dysmenorrhea-like
Diaphoresis
pain
Dizziness
Paresthesia
Blurred vision
Backache
Epigastric pain
Muscular pain
Excessive thirst
Breast tenderness
Twitching eyelids
6
Reference ID: 3420404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Eye pain
Gagging, retching
Drowsiness
Dry throat
Dystonia
Sensation of choking
Asthma
Thyroid storm
Injection site pain
Syncope
Tinnitus
Palpitations
Vertigo
Rash
Vaso-vagal syndrome
Upper respiratory
Dryness of mouth
infection
Hyperventilation
Leg cramps
Respiratory distress
Perforated uterus
Hematemesis
Anxiety
Taste alterations
Chest pain
Urinary tract infection
Retained placental
Septic shock
fragment
Torticollis
Shortness of breath
Lethargy
Fullness of throat
Hypertension
Uterine sacculation
Tachycardia
Faintness, light-
Pulmonary edema
headedness
Endometritis from
Uterine rupture
IUCD
The most common complications when HEMABATE was utilized for abortion requiring
additional treatment after discharge from the hospital were endometritis, retained
placental fragments, and excessive uterine bleeding, occurring in about one in every 50
patients.
Post-marketing experience:
Hypersensitivity reactions (e.g. Anaphylactic reaction, Anaphylactic shock,
Anaphylactoid reaction, Angioedema).
DOSAGE AND ADMINISTRATION
1. Abortion and Indications 1–4
An initial dose of 1 mL of HEMABATE Sterile Solution (containing the equivalent of
250 micrograms of carboprost) is to be administered deep in the muscle with a tuberculin
syringe. Subsequent doses of 250 micrograms should be administered at 1½ to 3½ hour
intervals depending on uterine response.
An optional test dose of 100 micrograms (0.4 mL) may be administered initially. The
dose may be increased to 500 micrograms (2 mL) if uterine contractility is judged to be
inadequate after several doses of 250 micrograms (1 mL).
7
Reference ID: 3420404
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The total dose administered of carboprost tromethamine should not exceed 12 milligrams
and continuous administration of the drug for more than two days is not recommended.
2. For Refractory Postpartum Uterine Bleeding:
An initial dose of 250 micrograms of HEMABATE Sterile Solution (1 mL of
HEMABATE) is to be given deep, intramuscularly. In clinical trials it was found that the
majority of successful cases (73%) responded to single injections. In some selected cases,
however, multiple dosing at intervals of 15 to 90 minutes was carried out with successful
outcome. The need for additional injections and the interval at which these should be
given can be determined only by the attending physicians as dictated by the course of
clinical events. The total dose of HEMABATE should not exceed 2 milligrams (8 doses).
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
HOW SUPPLIED
HEMABATE Sterile Solution is available in the following packages:
1 mL ampoules
NDC 0009-0856-05
10 x 1 mL ampoules
NDC 0009-0856-08
Each mL of HEMABATE contains carboprost tromethamine equivalent to 250 mcg of
carboprost.
HEMABATE must be refrigerated at 2° to 8° C (36° to 46° F).
1Duff, Sanders, and Gibbs; The course of labor in term patients with chorioamnionitis;
Am. J. Obstet. Gynecol.; vol. 147, no. 4, October 15, 1983 pp 391–395.
This product’s label may have been updated. For current full prescribing information,
please visit www.pfizer.com
Rx only company logo
LAB-0032-5.0
Revised December 2013
Reference ID: 3420404
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:44:26.343681
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017989s019lbl.pdf', 'application_number': 17989, 'submission_type': 'SUPPL ', 'submission_number': 19}
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11,108
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PSORCON® E Emollient Ointment
(diflorasone diacetate ointment) 0.05%
Prescribing Information as of December 2001.
Not For Ophthalmic Use
DESCRIPTION
Each gram of Psorcon E Emollient Ointment contains 0.5 mg diflorasone diacetate in an ointment base.
Chemically, diflorasone diacetate is: 6α,9-difluoro - 11β,17,21 - trihydroxy - 16β - methyl-pregna -
1,4 - diene - 3,20 - dione 17,21- diacetate. The structural formula is represented below:
Psorcon E Emollient Ointment contains diflorasone diacetate in an emollient, occlusive base
consisting of polyoxypropylene 15-stearyl ether, stearic acid, lanolin alcohol and white petrolatum.
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions.
The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various
laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies
and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a
recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.
Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined
by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive
dressings.
Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease
processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase
the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable
therapeutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION.)
Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic
pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma
proteins in varying degrees. They are metabolized primarily in the liver and are then excreted by the
kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
0817503005
O
CH3
F
F H
H
HO
H
H
CH3
CH3
H
OCCH3
O
C
O
CH2OCCH3
O
50065610
Prescribing Information as of December 2001.
Emollient Ointment
diflorasonediacetate
ointment
0.05%
®
™
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Layout and/or size adjusted for ease
of reading and printing.
INDICATIONS AND USAGE
Topical corticosteroids are indicated for relief of the inflammatory and pruritic manifestations of
corticosteroid responsive dermatoses.
CONTRAINDICATIONS
Topical steroids are contraindicated in those patients with a history of hypersensitivity to any of
the components of the preparation.
PRECAUTIONS
General: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-
pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia,
and glucosuria in some patients.
Conditions which augment systemic absorption include the application of the more potent
steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings.
Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area
or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppres-
sion by using the urinary free cortisol and ACTH stimulation tests. If HPA axis suppression is noted,
an attempt should be made to withdraw the drug, to reduce the frequency of application, or to
substitute a less potent steroid.
Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.
Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental
systemic corticosteroids.
Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be
more susceptible to systemic toxicity. (See PRECAUTIONS: Pediatric Use.)
If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial
agent should be instituted. If a favorable response does not occur promptly, the corticosteroid
should be discontinued until the infection has been adequately controlled.
Information for the Patient: Patients using topical corticosteroids should receive the following
information and instructions:
1. This medication is to be used as directed by the physician. It is for external use only. Avoid
contact with the eyes.
2. Patients should be advised not to use this medication for any disorder other than for which it
was prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlu-
sive unless directed by the physician.
4. Patients should report any signs of local adverse reactions especially under occlusive dressing.
5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants
on an infant or child being treated in the diaper area, as these garments may constitute occlu-
sive dressings.
Laboratory Tests: The following tests may be helpful in evaluating the HPA axis suppression:
Urinary free cortisol test
ACTH stimulation test
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal studies have not been
performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results.
Pregnancy Category C: Corticosteroids are generally teratogenic in laboratory animals when
administered systemically at relatively low dosage levels. The more potent corticosteroids have
been shown to be teratogenic after dermal application in laboratory animals. There are no
adequate and well-controlled studies in pregnant women on teratogenic effects from topically
applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used
extensively on pregnant patients, in large amounts, or for prolonged periods of time.
Nursing Mothers: It is not known whether topical administration of corticosteroids could result in
sufficient systemic absorption to produce detectable quantities in breast milk. Systemically admin-
istered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious
effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are
administered to a nursing woman.
Pediatric Use: Safety and effectiveness of Psorcon E (diflorasone diacetate ointment) in pediatric
patients have not been established. Because of a higher ratio of skin surface area to body mass,
pediatric patients are at a greater risk than adults of HPA-axis suppression when they are treated with
topical corticosteroids. They are, therefore, also at greater risk of glucocorticosteroid insufficiency after
withdrawal of treatment and of Cushing’s syndrome while on treatment. Adverse effects including
striae have been reported with inappropriate use of topical corticosteroids in pediatric patients.
HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in
pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in
pediatric patients include linear growth retardation, delayed weight gain, low plasma cortisol
levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension
include bulging fontanelles, headaches, and bilateral papilledema.
ADVERSE REACTIONS
The following local adverse reactions have been reported with topical corticosteroids, but may
occur more frequently with the use of occlusive dressings. These reactions are listed in an approx-
imate decreasing order of occurrence:
1.
Burning
9.
Perioral dermatitis
2.
Itching
10.
Allergic contact dermatitis
3.
Irritation
11.
Maceration of the skin
4.
Dryness
12.
Secondary infection
5.
Folliculitis
13.
Skin atrophy
6.
Hypertrichosis
14.
Striae
7.
Acneiform eruptions
15.
Miliaria
8.
Hypopigmentation
OVERDOSAGE
Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic
effects. (See PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Topical corticosteroids should be applied to the affected area as a thin film from one to four times
daily depending on the severity of the condition.
Occlusive dressings may be used for the management of psoriasis or recalcitrant conditions.
If an infection develops, the use of occlusive dressings should be discontinued and appropriate
antimicrobial therapy initiated.
HOW SUPPLIED
Psorcon E Emollient Ointment is available as follows:
15 gram tube
NDC 0066–0275–17
30 gram tube
NDC 0066–0275–31
60 gram tube
NDC 0066–0275–60
Store at controlled room temperature, 20° to 25° C (68° to 77° F) [see USP].
Prescribing Information as of December 2001.
Rx only
Manufactured for
Dermik Laboratories, Inc.
Berwyn, PA USA 19312
By Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI, USA 49001
Revised December 2001
817 503 005
50065610
691694
PSORCON® E Emollient Ointment
(diflorasone diacetate ointment) 0.05%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:26.471041
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/17994slr022_psorcon_lbl.pdf', 'application_number': 17994, 'submission_type': 'SUPPL ', 'submission_number': 22}
|
11,105
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1
Rev 04-15-04
NOLVADEX
(Tamoxifen Citrate)
TABLETS
WARNING - For Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk
for Breast Cancer: Serious and life-threatening events associated with NOLVADEX in the risk
reduction setting (women at high risk for cancer and women with DCIS) include uterine
malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated
from the NSABP P-1 trial (see CLINICAL PHARMACOLOGY-Clinical Studies –
Reduction in Breast Cancer Incidence In High Risk Women). Uterine malignancies consist
of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for
NOLVADEX vs 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women-years
of 0.17 for NOLVADEX vs 0.0 for placebo)*. For stroke, the incidence rate per 1,000 women-
years was 1.43 for NOLVADEX vs 1.00 for placebo**. For pulmonary embolism, the incidence
rate per 1,000 women-years was 0.75 for NOLVADEX versus 0.25 for placebo**.
Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.
Health care providers should discuss the potential benefits versus the potential risks of these
serious events with women at high risk of breast cancer and women with DCIS considering
NOLVADEX to reduce their risk of developing breast cancer.
The benefits of NOLVADEX outweigh its risks in women already diagnosed with breast cancer.
*Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1
study. See WARNINGS: Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma.
**See Table 3 under CLINICAL PHARMACOLOGY-Clinical Studies.
DESCRIPTION
NOLVADEX® (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral
administration. NOLVADEX Tablets are available as:
10 mg Tablets:
Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen.
20 mg Tablets:
Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen.
Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.
Chemically, NOLVADEX is the trans-isomer of a triphenylethylene derivative. The chemical
name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3-
propanetricarboxylate (1:1). The structural and empirical formulas are:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
(C32H37NO8)
Tamoxifen citrate has a molecular weight of 563.62, the pKa’ is 8.85, the equilibrium solubility
in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.
CLINICAL PHARMACOLOGY
NOLVADEX is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in
animal test systems. The antiestrogenic effects may be related to its ability to compete with
estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat
mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of
already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its
antitumor effects by binding the estrogen receptors.
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for
estrogen receptor protein.
Absorption and Distribution:
Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40
ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in
plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to
7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range
10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to
patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183
ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The
average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after
administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL)
and 353 ng/mL (range 152-706 ng/mL), respectively. After initiation of therapy, steady state
concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for
N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately
14 days for this metabolite. In a steady-state, crossover study of 10 mg NOLVADEX tablets
given twice a day vs. a 20 mg NOLVADEX tablet given once daily, the 20 mg NOLVADEX
tablet was bioequivalent to the 10 mg NOLVADEX tablets.
Metabolism:
Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the
major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen
appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol
derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a
substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Excretion:
Studies in women receiving 20 mg of 14C tamoxifen have shown that approximately 65% of the
administered dose was excreted from the body over a period of 2 weeks with fecal excretion as
the primary route of elimination. The drug is excreted mainly as polar conjugates, with
unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal
radioactivity.
Special Populations:
The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been
determined. The effects of reduced liver function on the metabolism and pharmacokinetics of
tamoxifen have not been determined.
Pediatric Patients:
The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a
population pharmacokinetic analysis with sparse samples per patient obtained from 27 female
pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy,
and pharmacokinetics of NOLVADEX in treating McCune-Albright Syndrome. Rich data from
two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast
cancer completed the studies were included in the analysis to determine the structural
pharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the
data.
In pediatric patients, an average steady state peak plasma concentration (Css, max) and AUC were
of 187 ng/mL and 4110 ng hr/mL, respectively, and Css, max occurred approximately 8 hours after
dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was
approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of
female pediatric patients (2-6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7-10.9
year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was
comparable between the pediatric and adult patients. The safety and efficacy of NOLVADEX
for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty
have not been studied beyond one year of treatment. The long-term effects of NOLVADEX
therapy in girls have not been established. In adults treated with NOLVADEX an increase in
incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see BOXED
WARNING).
Drug-Drug Interactions:
In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively
inhibited formation of N-desmethyl tamoxifen with apparent K1 of 20, 1, 45 and 30 µM,
respectively. The clinical significance of these in vitro studies is unknown.
Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-
administered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by
86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen
plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but
not tamoxifen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Clinical Studies
Metastatic Breast Cancer:
Premenopausal Women (NOLVADEX vs. Ablation):
Three prospective, randomized studies (Ingle, Pritchard, Buchanan) compared NOLVADEX to
ovarian ablation (oophorectomy or ovarian irradiation) in premenopausal women with advanced
breast cancer. Although the objective response rate, time to treatment failure, and survival were
similar with both treatments, the limited patient accrual prevented a demonstration of
equivalence. In an overview analysis of survival data from the 3 studies, the hazard ratio for
death (NOLVADEX/ovarian ablation) was 1.00 with two-sided 95% confidence intervals of 0.73
to 1.37. Elevated serum and plasma estrogens have been observed in premenopausal women
receiving NOLVADEX, but the data from the randomized studies do not suggest an adverse
effect of this increase. A limited number of premenopausal patients with disease progression
during NOLVADEX therapy responded to subsequent ovarian ablation.
Male Breast Cancer:
Published results from 122 patients (119 evaluable) and case reports in 16 patients (13 evaluable)
treated with NOLVADEX have shown that NOLVADEX is effective for the palliative treatment
of male breast cancer. Sixty-six of these 132 evaluable patients responded to NOLVADEX
which constitutes a 50% objective response rate.
Adjuvant Breast Cancer:
Overview:
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted worldwide
overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, and again in 1995.
In 1998, 10-year outcome data were reported for 36,689 women in 55 randomized trials of
adjuvant NOLVADEX using doses of 20-40 mg/day for 1-5+ years. Twenty-five percent of
patients received 1 year or less of trial treatment, 52% received 2 years, and 23% received about
5 years. Forty-eight percent of tumors were estrogen receptor (ER) positive (> 10 fmol/mg),
21% were ER poor (< 10 fmol/l), and 31% were ER unknown. Among 29,441 patients with ER
positive or unknown breast cancer, 58% were entered into trials comparing NOLVADEX to no
adjuvant therapy and 42% were entered into trials comparing NOLVADEX in combination with
chemotherapy vs. the same chemotherapy alone. Among these patients, 54% had node positive
disease and 46% had node negative disease.
Among women with ER positive or unknown breast cancer and positive nodes who received
about 5 years of treatment, overall survival at 10 years was 61.4% for NOLVADEX vs. 50.5%
for control (logrank 2p < 0.00001). The recurrence-free rate at 10 years was 59.7% for
NOLVADEX vs. 44.5% for control (logrank 2p < 0.00001). Among women with ER positive or
unknown breast cancer and negative nodes who received about 5 years of treatment, overall
survival at 10 years was 78.9% for NOLVADEX vs. 73.3% for control (logrank 2p < 0.00001).
The recurrence-free rate at 10 years was 79.2% for NOLVADEX versus 64.3% for control
(logrank 2p < 0.00001).
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The effect of the scheduled duration of tamoxifen may be described as follows. In women with
ER positive or unknown breast cancer receiving 1 year or less, 2 years or about 5 years of
NOLVADEX, the proportional reductions in mortality were 12%, 17% and 26%, respectively
(trend significant at 2p < 0.003). The corresponding reductions in breast cancer recurrence were
21%, 29% and 47% (trend significant at 2p < 0.00001).
Benefit is less clear for women with ER poor breast cancer in whom the proportional reduction
in recurrence was 10% (2p = 0.007) for all durations taken together, or 9% (2p = 0.02) if
contralateral breast cancers are excluded. The corresponding reduction in mortality was 6%
(NS). The effects of about 5 years of NOLVADEX on recurrence and mortality were similar
regardless of age and concurrent chemotherapy. There was no indication that doses greater than
20 mg per day were more effective.
Node Positive - Individual Studies:
Two studies (Hubay and NSABP B-09) demonstrated an improved disease-free survival
following radical or modified radical mastectomy in postmenopausal women or women 50 years
of age or older with surgically curable breast cancer with positive axillary nodes when
NOLVADEX was added to adjuvant cytotoxic chemotherapy. In the Hubay study,
NOLVADEX was added to "low-dose" CMF (cyclophosphamide, methotrexate and
fluorouracil). In the NSABP B-09 study, NOLVADEX was added to melphalan [L-
phenylalanine mustard (P)] and fluorouracil (F).
In the Hubay study, patients with a positive (more than 3 fmol) estrogen receptor were more
likely to benefit. In the NSABP B-09 study in women age 50-59 years, only women with both
estrogen and progesterone receptor levels 10 fmol or greater clearly benefited, while there was a
nonstatistically significant trend toward adverse effect in women with both estrogen and
progesterone receptor levels less than 10 fmol. In women age 60-70 years, there was a trend
toward a beneficial effect of NOLVADEX without any clear relationship to estrogen or
progesterone receptor status.
Three prospective studies (ECOG-1178, Toronto, NATO) using NOLVADEX adjuvantly as a
single agent demonstrated an improved disease-free survival following total mastectomy and
axillary dissection for postmenopausal women with positive axillary nodes compared to
placebo/no treatment controls. The NATO study also demonstrated an overall survival benefit.
Node Negative - Individual Studies:
NSABP B-14, a prospective, double-blind, randomized study, compared NOLVADEX to
placebo in women with axillary node-negative, estrogen-receptor positive (10 fmol/mg cytosol
protein) breast cancer (as adjuvant therapy, following total mastectomy and axillary dissection,
or segmental resection, axillary dissection, and breast radiation). After five years of treatment,
there was a significant improvement in disease-free survival in women receiving NOLVADEX.
This benefit was apparent both in women under age 50 and in women at or beyond age 50.
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One additional randomized study (NATO) demonstrated improved disease-free survival for
NOLVADEX compared to no adjuvant therapy following total mastectomy and axillary
dissection in postmenopausal women with axillary node-negative breast cancer. In this study,
the benefits of NOLVADEX appeared to be independent of estrogen receptor status.
Duration of Therapy:
In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those
studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter
period of therapy.
In the NSABP B-14 trial, in which patients were randomized to NOLVADEX 20 mg/day for 5
years vs. placebo and were disease-free at the end of this 5-year period were offered
rerandomization to an additional 5 years of NOLVADEX or placebo. With 4 years of follow-up
after this rerandomization, 92% of the women that received 5 years of NOLVADEX were alive
and disease-free, compared to 86% of the women scheduled to receive 10 years of NOLVADEX
(p=0.003). Overall survivals were 96% and 94%, respectively (p=0.08). Results of the B-14
study suggest that continuation of therapy beyond 5 years does not provide additional benefit.
A Scottish trial of 5 years of tamoxifen vs. indefinite treatment found a disease-free survival of
70% in the five-year group and 61% in the indefinite group, with 6.2 years median follow-up
(HR=1.27, 95% CI 0.87-1.85).
In a large randomized trial conducted by the Swedish Breast Cancer Cooperative Group of
adjuvant NOLVADEX 40 mg/day for 2 or 5 years, overall survival at 10 years was estimated to
be 80% in the patients in the 5-year tamoxifen group, compared with 74% among corresponding
patients in the 2-year treatment group (p=0.03). Disease-free survival at 10 years was 73% in the
5-year group and 67% in the 2-year group (p=0.009). Compared with 2 years of tamoxifen
treatment, 5 years of treatment resulted in a slightly greater reduction in the incidence of
contralateral breast cancer at 10 years, but this difference was not statistically significant.
Contralateral Breast Cancer:
The incidence of contralateral breast cancer is reduced in breast cancer patients (premenopausal
and postmenopausal) receiving NOLVADEX compared to placebo. Data on contralateral breast
cancer are available from 32,422 out of 36,689 patients in the 1995 overview analysis of the
Early Breast Cancer Trialists Collaborative Group (EBCTCG). In clinical trials with
NOLVADEX of 1 year or less, 2 years, and about 5 years duration, the proportional reductions
in the incidence rate of contralateral breast cancer among women receiving NOLVADEX were
13% (NS), 26% (2p = 0.004) and 47% (2p < 0.00001), with a significant trend favoring longer
tamoxifen duration (2p = 0.008). The proportional reductions in the incidence of contralateral
breast cancer were independent of age and ER status of the primary tumor. Treatment with about
5 years of NOLVADEX reduced the annual incidence rate of contralateral breast cancer from 7.6
per 1,000 patients in the control group compared with 3.9 per 1,000 patients in the tamoxifen
group.
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In a large randomized trial in Sweden (the Stockholm Trial) of adjuvant NOLVADEX 40
mg/day for 2-5 years, the incidence of second primary breast tumors was reduced 40% (p <
0.008) on tamoxifen compared to control. In the NSABP B-14 trial in which patients were
randomized to NOLVADEX 20 mg/day for 5 years vs. placebo, the incidence of second primary
breast cancers was also significantly reduced (p < 0.01). In NSABP B-14, the annual rate of
contralateral breast cancer was 8.0 per 1000 patients in the placebo group compared with 5.0 per
1,000 patients in the tamoxifen group, at 10 years after first randomization.
Ductal Carcinoma in Situ:
NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ
(DCIS). This trial compared the addition of NOLVADEX or placebo to treatment with
lumpectomy and radiation therapy for women with DCIS. The primary objective was to
determine whether 5 years of NOLVADEX therapy (20 mg/day) would reduce the incidence of
invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast.
In this trial 1,804 women were randomized to receive either NOLVADEX or placebo for 5 years:
902 women were randomized to NOLVADEX 10 mg tablets twice a day and 902 women were
randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798
women and the median duration of follow-up was 74 months.
The NOLVADEX and placebo groups were well balanced for baseline demographic and
prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum
dimension, were not palpable, and were detected by mammography alone. Over 60% of the
study population was postmenopausal. In 16% of patients, the margin of the resected specimen
was reported as being positive after surgery. Approximately half of the tumors were reported to
contain comedo necrosis.
For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among
women assigned to NOLVADEX (44 cases - NOLVADEX, 74 cases - placebo; p=0.004; relative
risk (RR)=0.57, 95% CI: 0.39-0.84). No data are available regarding the ER status of the
invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that
reported annually in the SEER data base.
Results are shown in Table 1. For each endpoint the following results are presented: the number
of events and rate per 1,000 women per year for the placebo and NOLVADEX groups; and the
relative risk (RR) and its associated 95% confidence interval (CI) between NOLVADEX and
placebo. Relative risks less than 1.0 indicate a benefit of NOLVADEX therapy. The limits of
the confidence intervals can be used to assess the statistical significance of the benefits of
NOLVADEX therapy. If the upper limit of the CI is less than 1.0, then a statistically significant
benefit exists.
Table 1. Major Outcomes of the NSABP B-24 Trial
Type of
Event
Lumpectomy,
radiotherapy, and placebo
Lumpectomy,
radiotherapy, and NOLVADEX
RR
95% CI Limits
No. of
events
Rate per 1000
women per year
No. of
events
Rate per 1000
women per year
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8
Invasive
breast cancer
(Primary
endpoint)
74
16.73
44
9.60
0.57
0.39 to 0.84
-Ipsilateral
47
10.61
27
5.90
0.56
0.33 to 0.91
-Contralateral
25
5.64
17
3.71
0.66
0.33 to 1.27
-Side
undertermined
2
--
0
--
--
Secondary Endpoints
DCIS
56
12.66
41
8.95
0.71
0.46 to 1.08
-Ipsilateral
46
10.40
38
8.29
0.88
0.51 to 1.25
-Contralateral
10
2.26
3
0.65
0.29
0.05 to 1.13
All Breast
Cancer Events
129
29.16
84
18.34
0.63
0.47 to 0.83
-All ipsilateral
events
96
21.70
65
14.19
0.65
0.47 to 0.91
-All contralateral
events
37
8.36
20
4.37
0.52
0.29 to 0.92
Deaths
32
28
Uterine
Malignancies1
4
9
Endometrial
Adenocarcinoma1
4
0.57
8
1.15
Uterine Sarcoma1
0
0.0
1
0.14
Second primary
malignancies
(other than
endometrial
and breast)
30
29
Stroke
2
7
Thromboembolic
events
(DVT, PE)
5
15
1Updated follow-up data (median 8.1 years)
Survival was similar in the placebo and NOLVADEX groups. At 5 years from study entry,
survival was 97% for both groups.
Reduction in Breast Cancer Incidence in High Risk Women:
The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized,
placebo-controlled trial with a primary objective to determine whether 5 years of NOLVADEX
therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk
for the disease (See INDICATIONS AND USAGE). Secondary objectives included an
evaluation of the incidence of ischemic heart disease; the effects on the incidence of bone
fractures; and other events that might be associated with the use of NOLVADEX, including:
endometrial cancer, pulmonary embolus, deep vein thrombosis, stroke, and cataract formation
and surgery (See WARNINGS).
The Gail Model was used to calculate predicted breast cancer risk for women who were less than
60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors
were used: age; number of first-degree female relatives with breast cancer; previous breast
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biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age
at menarche. A 5-year predicted risk of breast cancer of 1.67% was required for entry into the
trial.
In this trial, 13,388 women of at least 35 years of age were randomized to receive either
NOLVADEX or placebo for five years. The median duration of treatment was 3.5 years. As of
January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of
women randomized to placebo (1,782) and 24% of women randomized to NOLVADEX (1,596)
completed 5 years of therapy. The demographic characteristics of women on the trial with
follow-up data are shown in Table 2.
Table 2. Demographic Characteristics of Women in the NSABP P-1 Trial
Characteristic
Placebo
Tamoxifen
#
%
#
%
Age (yrs.)
35-39
184
3
158
2
40-49
2,394
36
2,411
37
50-59
2,011
31
2,019
31
60-69
1,588
24
1,563
24
70
393
6
393
6
Age at first live birth (yrs.)
Nulliparous
1,202
18
1,205
18
12-19
915
14
946
15
20-24
2,448
37
2,449
37
25-29
1,399
21
1,367
21
30
606
9
577
9
Race
White
6,333
96
6,323
96
Black
109
2
103
2
Other
128
2
118
2
Age at menarche
14
1,243
19
1,170
18
12-13
3,610
55
3,610
55
11
1,717
26
1,764
27
# of first degree relatives with breast cancer
0
1,584
24
1,525
23
1
3,714
57
3,744
57
2+
1,272
19
1,275
20
Prior Hysterectomy
No
4,173
63.5
4,018
62.4
Yes
2,397
36.5
2,464
37.7
# of previous breast biopsies
0
2,935
45
2,923
45
1
1,833
28
1,850
28
2
1,802
27
1,771
27
History of atypical hyperplasia in the breast
No
5,958
91
5,969
91
Yes
612
9
575
9
History of LCIS at entry
No
6,165
94
6,135
94
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Yes
405
6
409
6
5-year predicted breast cancer risk (%)
2.00
1,646
25
1,626
25
2.01-3.00
2,028
31
2,057
31
3.01-5.00
1,787
27
1,707
26
5.01
1,109
17
1,162
18
Total
6,570
100.0
6,544
100.0
Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive
breast cancer was reduced by 44% among women assigned to NOLVADEX (86 cases-
NOLVADEX, 156 cases-placebo; p<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A
reduction in the incidence of breast cancer was seen in each prospectively specified age group
( 49, 50-59, 60), in women with or without LCIS, and in each of the absolute risk levels
specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ
(DCIS) was seen (23-NOLVADEX, 35-placebo; RR=0.66; 95% CI: 0.39-1.11).
There was no statistically significant difference in the number of myocardial infarctions, severe
angina, or acute ischemic cardiac events between the two groups (61-NOLVADEX, 59-placebo;
RR=1.04, 95% CI: 0.73-1.49).
No overall difference in mortality (53 deaths in NOLVADEX group vs. 65 deaths in placebo
group) was present. No difference in breast cancer-related mortality was observed (4 deaths in
NOLVADEX group vs. 5 deaths in placebo group).
Although there was a non-significant reduction in the number of hip fractures (9 on
NOLVADEX, 20 on placebo) in the NOLVADEX group, the number of wrist fractures was
similar in the two treatment groups (69 on NOLVADEX, 74 on placebo). A subgroup analysis
of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to
menopausal status in patients receiving NOLVADEX. In postmenopausal women there was no
evidence of bone loss of the lumbar spine and hip. Conversely, NOLVADEX was associated
with significant bone loss of the lumbar spine and hip in premenopausal women.
The risks of NOLVADEX therapy include endometrial cancer, DVT, PE, stroke, cataract
formation and cataract surgery (See Table 3). In the NSABP P-1 trial, 33 cases of endometrial
cancer were observed in the NOLVADEX group vs. 14 in the placebo group (RR=2.48, 95% CI:
1.27-4.92). Deep vein thrombosis was observed in 30 women receiving NOLVADEX vs. 19 in
women receiving placebo (RR=1.59, 95% CI: 0.86-2.98). Eighteen cases of pulmonary
embolism were observed in the NOLVADEX group vs. 6 in the placebo group (RR=3.01, 95%
CI: 1.15-9.27). There were 34 strokes on the NOLVADEX arm and 24 on the placebo arm
(RR=1.42; 95% CI: 0.82-2.51). Cataract formation in women without cataracts at baseline was
observed in 540 women taking NOLVADEX vs. 483 women receiving placebo (RR=1.13, 95%
CI: 1.00-1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201
women taking NOLVADEX vs. 129 women receiving placebo (RR=1.51, 95% CI: 1.21-1.89)
(See WARNINGS).
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Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the
following results are presented: the number of events and rate per 1000 women per year for the
placebo and NOLVADEX groups; and the relative risk (RR) and its associated 95% confidence
interval (CI) between NOLVADEX and placebo. Relative risks less than 1.0 indicate a benefit
of NOLVADEX therapy. The limits of the confidence intervals can be used to assess the
statistical significance of the benefits or risks of NOLVADEX therapy. If the upper limit of the
CI is less than 1.0, then a statistically significant benefit exists.
For most participants, multiple risk factors would have been required for eligibility. This table
considers risk factors individually, regardless of other co-existing risk factors, for women who
developed breast cancer. The 5-year predicted absolute breast cancer risk accounts for multiple
risk factors in an individual and should provide the best estimate of individual benefit (See
INDICATIONS AND USAGE).
Table 3. Major Outcomes of the NSABP P-1 Trial
# OF EVENTS
RATE/1000 WOMEN/YEAR
95% CI
TYPE OF EVENT
PLACEBO
NOLVADEX
PLACEBO
NOLVADEX
RR
LIMITS
Invasive Breast Cancer
156
86
6.49
3.58
0.56
0.43-0.72
Age 49
59
38
6.34
4.11
0.65
0.43-0.98
Age 50-59
46
25
6.31
3.53
0.56
0.35-0.91
Age 60
51
23
7.17
3.22
0.45
0.27-0.74
Risk Factors for Breast Cancer
History, LCIS
No
140
78
6.23
3.51
0.56
0.43-0.74
Yes
16
8
12.73
6.33
0.50
0.21-1.17
History, Atypical Hyperplasia
No
1.38
84
6.37
3.89
0.61
0.47-0.80
Yes
18
2
8.69
1.05
0.12
0.03-0.52
No. First Degree Relatives
0
32
17
5.97
3.26
0.55
0.30-0.98
1
80
45
5.81
3.31
0.57
0.40-0.82
2
35
18
8.92
4.67
0.52
0.30-0.92
3
9
6
13.33
7.58
0.57
0.20-1.59
5-Year Predicted Breast Cancer Risk
(as calculated by the Gail Model)
2.00%
31
13
5.36
2.26
0.42
0.22-0.81
2.01-3.00%
39
28
5.25
3.83
0.73
0.45-1.18
3.01-5.00%
36
26
5.37
4.06
0.76
0.46-1.26
5.00%
50
19
13.15
4.71
0.36
0.21-0.61
DCIS
35
23
1.47
0.97
0.66
0.39-1.11
Fractures (protocol-specified sites)
921
761
3.87
3.20
0.61
0.83-1.12
Hip
20
9
0.84
0.38
0.45
0.18-1.04
Wrist2
74
69
3.11
2.91
0.93
0.67-1.29
Total Ischemic Events
59
61
2.47
2.57
1.04
0.71-1.51
Myocardial Infarction
27
27
1.13
1.13
1.00
0.57-1.78
Fatal
8
7
0.33
0.29
0.88
0.27-2.77
Nonfatal
19
20
0.79
0.84
1.06
0.54-2.09
Angina3
12
12
0.50
0.50
1.00
0.41-2.44
Acute Ischemic Syndrome4
20
22
0.84
0.92
1.11
0.58-2.13
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Uterine Malignancies (among
women with an intact uterus)10
17
57
Endometrial Adenocarcinoma10
17
53
0.71
2.20
Uterine Sarcoma10
0
4
0.0
0.17
Stroke5
24
34
1.00
1.43
1.42
0.82-2.51
Transient Ischemic Attack
21
18
0.88
0.75
0.86
0.43-1.70
Pulmonary Emboli6
6
18
0.25
0.75
3.01
1.15-9.27
Deep-Vein Thrombosis7
19
30
0.79
1.26
1.59
0.86-2.98
Cataracts Developing on Study8
483
540
22.51
25.41
1.13
1.00-1.28
Underwent Cataract Surgery8
63
101
2.83
4.57
1.62
1.18-2.22
Underwent Cataract Surgery9
1.29
201
5.44
8.56
1.58
1.26-1.97
1Two women had hip and wrist fractures
2 Includes Colles’ and other lower radius fractures
3Requiring angioplasty or CABG
4New Q-wave on ECG; no angina or elevation of serum enzymes; or angina requiring
hospitalization without surgery
5Seven cases were fatal; three in the placebo group and four in the NOLVADEX group
6Three cases in the NOLVADEX group were fatal
7All but three cases in each group required hospitalization
8Based on women without cataracts at baseline (6,230-Placebo, 6,199-NOLVADEX)
9All women (6,707-Placebo, 6,681-NOLVADEX)
10Updated long-term follow-up data (median 6.9 years) from NSABP P-1 study
added after cut-off for the other information in this table.
Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes
tumor size, nodal status, ER status. NOLVADEX decreased the incidence of small estrogen
receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or
larger tumors.
Table 4. Characteristics of Breast Cancer in NSABP P-1 Trial
Staging Parameter
Placebo
N=156
Tamoxifen
N=86
Total
N=242
Tumor Size:
T1
117
60
177
T2
28
20
48
T3
7
3
10
T4
1
2
3
Unknown
3
1
4
Nodal status:
Negative
103
56
159
1-3 positive nodes
29
14
43
4 positive nodes
10
12
22
Unknown
14
4
18
Stage:
I
88
47
135
II: node negative
15
9
24
II: node positive
33
22
55
III
6
4
10
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IV
21
1
3
Unknown
12
3
15
Estrogen receptor:
Positive
115
38
153
Negative
27
36
63
Unknown
14
12
26
1One participant presented with a suspicious bone scan but did not have documented metastases. She subsequently
died of metastatic breast cancer.
Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of
tamoxifen in reducing breast cancer incidence have been reported.
The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35
and 70, who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or
matching placebo for 5 years. The primary endpoints were occurrence of, and death from,
invasive breast cancer. Women without any specific risk factors for breast cancer were to be
entered. Between 1992 and 1997, 5408 women were randomized. Hormone Replacement
Therapy (HRT) was used in 14% of participants. The trial closed in 1997 due to the large
number of dropouts during the first year of treatment (26%). After 46 months of follow-up there
were 22 breast cancers in women on placebo and 19 in women on tamoxifen. Although no
decrease in breast cancer incidence was observed, there was a trend for a reduction in breast
cancer among women receiving protocol therapy for at least 1 year (19-placebo, 11- tamoxifen).
The small numbers of participants along with the low level of risk in this otherwise healthy
group precluded an adequate assessment of the effect of tamoxifen in reducing the incidence of
breast cancer.
The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT
was begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial
was subsequently extended to a pilot trial to accrue additional participants to further assess the
safety of tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986
and 1996; they were selected on the basis of a family history of breast cancer. HRT was used in
40% of participants. In this trial, with a 70 month median follow-up, 34 and 36 breast cancers (8
noninvasive, 4 on each arm) were observed among women on tamoxifen and placebo,
respectively. Patients in this trial were younger than those in the NSABP P-1 trial and may have
been more likely to develop ER (-) tumors, which are unlikely to be reduced in number by
tamoxifen therapy. Although women were selected on the basis of family history and were
thought to have a high risk of breast cancer, few events occurred, reducing the statistical power
of the study. These factors are potential reasons why the RMT may not have provided an
adequate assessment of the effectiveness of tamoxifen in reducing the incidence of breast cancer.
In these trials, an increased number of cases of deep vein thrombosis, pulmonary embolus,
stroke, and endometrial cancer were observed on the tamoxifen arm compared to the placebo
arm. The frequency of events was consistent with the safety data observed in the NSABP P-1
trial.
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14
McCune-Albright Syndrome:
A single, uncontrolled multicenter trial of NOLVADEX 20 mg once a day was conducted in a
heterogenous group of girls with McCune-Albright Syndrome and precocious puberty
manifested by physical signs of pubertal development, episodes of vaginal bleeding and/or
advanced bone age (bone age of at least 12 months beyond chronological age). Twenty-eight
female pediatric patients, aged 2 to 10 years, were treated for up to 12 months. Effect of
treatment on frequency of vaginal bleeding, bone age advancement, and linear growth rate was
assessed relative to prestudy baseline. NOLVADEX treatment was associated with a 50%
reduction in frequency of vaginal bleeding episodes by patient or family report (mean annualized
frequency of 3.56 episodes at baseline and 1.73 episodes on-treatment). Among the patients who
reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no
bleeding for a 6-month period and 33% (7 out of 21 patients) reported no vaginal bleeding for
the duration of the trial. Not all patients improved on treatment and a few patients not reporting
vaginal bleeding in the 6 months prior to enrollment reported menses on treatment.
NOLVADEX therapy was associated with a reduction in mean rate of increase of bone age.
Individual responses with regard to bone age advancement were highly heterogeneous. Linear
growth rate was reduced during the course of NOLVADEX treatment in a majority of patients
(mean change of 1.68 cm/year relative to baseline; change from 7.47 cm/year at baseline to
5.79 cm/year on study). This change was not uniformly seen across all stages of bone maturity;
all recorded response failures occurred in patients with bone ages less than 7 years at screening.
Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-
year study. A causal relationship has not been established; however, as an increase in the
incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated
with NOLVADEX (see BOXED WARNING), continued monitoring of McCune-Albright
patients treated with NOLVADEX for long-term uterine effects is recommended. The safety
and efficacy of NOLVADEX for girls aged two to 10 years with McCune-Albright
Syndrome and precocious puberty have not been studied beyond one year of treatment.
The long-term effects of NOLVADEX therapy in girls have not been established.
INDICATIONS AND USAGE
Metastatic Breast Cancer:
NOLVADEX is effective in the treatment of metastatic breast cancer in women and men. In
premenopausal women with metastatic breast cancer, NOLVADEX is an alternative to
oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors
are estrogen receptor positive are more likely to benefit from NOLVADEX therapy.
Adjuvant Treatment of Breast Cancer:
NOLVADEX is indicated for the treatment of node-positive breast cancer in postmenopausal
women following total mastectomy or segmental mastectomy, axillary dissection, and breast
irradiation. In some NOLVADEX adjuvant studies, most of the benefit to date has been in the
subgroup with four or more positive axillary nodes.
NOLVADEX is indicated for the treatment of axillary node-negative breast cancer in women
following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation.
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15
The estrogen and progesterone receptor values may help to predict whether adjuvant
NOLVADEX therapy is likely to be beneficial.
NOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant
NOLVADEX therapy for breast cancer.
Ductal Carcinoma in Situ (DCIS):
In women with DCIS, following breast surgery and radiation, NOLVADEX is indicated to
reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the
label). The decision regarding therapy with NOLVADEX for the reduction in breast cancer
incidence should be based upon an individual assessment of the benefits and risks of
NOLVADEX therapy.
Current data from clinical trials support five years of adjuvant NOLVADEX therapy for patients
with breast cancer.
Reduction in Breast Cancer Incidence in High Risk Women:
NOLVADEX is indicated to reduce the incidence of breast cancer in women at high risk for
breast cancer. This effect was shown in a study of 5 years planned duration with a median
follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The
longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or
breast cancer-related mortality (see BOXED WARNING at the beginning of the label).
NOLVADEX is indicated only for high-risk women. “High risk” is defined as women at least
35 years of age with a 5-year predicted risk of breast cancer 1.67%, as calculated by the Gail
Model.
Examples of combinations of factors predicting a 5-year risk 1.67% are:
Age 35 or older and any of the following combination of factors:
One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a
history of a breast biopsy showing atypical hyperplasia; or
At least 2 first degree relatives with a history of breast cancer, and a personal history of at
least one breast biopsy; or
LCIS
Age 40 or older and any of the following combination of factors:
One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first
live birth 25 or older, and age at menarche 11 or younger; or
At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or
younger; or
One first degree relative with a history of breast cancer, and a personal history of a breast
biopsy showing atypical hyperplasia.
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16
Age 45 or older and any of the following combination of factors:
At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or
younger; or
One first degree relative with a history of breast cancer with a personal history of a benign
breast biopsy, age at menarche 11 or less and age at first live birth 20 or more.
Age 50 or older and any of the following combination of factors:
At least 2 first degree relatives with a history of breast cancer; or
History of one breast biopsy showing atypical hyperplasia, and age at first live birth 30 or
older and age at menarche 11 or less; or
History of at least two breast biopsies with a history of atypical hyperplasia, and age at first
live birth 30 or more.
Age 55 or older and any of the following combination of factors:
One first degree relative with a history of breast cancer with a personal history of a benign
breast biopsy, and age at menarche 11 or less; or
History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live
birth 20 or older.
Age 60 or older and:
5-year predicted risk of breast cancer 1.67%, as calculated by the Gail Model.
For women whose risk factors are not described in the above examples, the Gail Model is
necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail
Model Risk Assessment Tool by dialing 1-800-544-2007.
There are insufficient data available regarding the effect of NOLVADEX on breast cancer
incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific
recommendations on the effectiveness of NOLVADEX in these patients.
After an assessment of the risk of developing breast cancer, the decision regarding therapy with
NOLVADEX for the reduction in breast cancer incidence should be based upon an individual
assessment of the benefits and risks of NOLVADEX therapy. In the NSABP P-1 trial,
NOLVADEX treatment lowered the risk of developing breast cancer during the follow-up period
of the trial, but did not eliminate breast cancer risk (See Table 3 in CLINICAL
PHARMACOLOGY).
CONTRAINDICATIONS
NOLVADEX is contraindicated in patients with known hypersensitivity to the drug or any of its
ingredients.
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17
Reduction in Breast Cancer Incidence in High Risk Women and Women with
DCIS:
NOLVADEX is contraindicated in women who require concomitant coumarin-type
anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary
embolus.
WARNINGS
Effects in Metastatic Breast Cancer Patients:
As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been
reported in some breast cancer patients with bone metastases within a few weeks of starting
treatment with NOLVADEX. If hypercalcemia does occur, appropriate measures should be taken
and, if severe, NOLVADEX should be discontinued.
Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma:
An increased incidence of uterine malignancies has been reported in association with
NOLVADEX treatment. The underlying mechanism is unknown, but may be related to the
estrogen-like effect of NOLVADEX. Most uterine malignancies seen in association with
NOLVADEX are classified as adenocarcinoma of the endometrium. However, rare uterine
sarcomas, including malignant mixed mullerian tumors, have also been reported. Uterine
sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis,
and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-
term users ( 2 years) of NOLVADEX than non-users. Some of the uterine malignancies
(endometrial carcinoma or uterine sarcoma) have been fatal.
In the NSABP P-1 trial, among participants randomized to NOLVADEX there was a statistically
significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial
cancer, compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI:
1.27-4.92). The 33 cases in participants receiving NOLVADEX were FIGO Stage I, including 20
IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13
were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on NOLVADEX
and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase
was primarily observed among women at least 50 years of age at the time of randomization (26
cases of invasive endometrial cancer, compared to 6 cases among participants randomized to
placebo (RR=4.50, 95% CI: 1.78-13.16). Among women 49 years of age at the time of
randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among
participants randomized to placebo (RR=0.94, 95% CI: 0.28-2.89). If age at the time of diagnosis
is considered, there were 4 cases of endometrial cancer among participants 49 randomized to
NOLVADEX compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-
12.0). For women 50 at the time of diagnosis, there were 29 cases among participants
randomized to NOLVADEX compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3-
4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger
women. Most (29 of 33 cases in the NOLVADEX group) endometrial cancers were diagnosed
in symptomatic women, although 5 of 33 cases in the NOLVADEX group occurred in
asymptomatic women. Among women receiving NOLVADEX the events appeared between 1
and 61 months (average=32 months) from the start of treatment.
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18
In an updated review of long-term data (median length of total follow-up is 6.9 years, including
blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1
risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was
increased in women taking NOLVADEX. During blinded follow-up, there were 36 cases of
FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women
receiving NOLVADEX and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA
and 5 IB), and 1 case was FIGO Stage IV]. Of the patients receiving NOLVADEX who
developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation
therapy. In the placebo group, one patient with FIGO Stage 1B cancer received radiation therapy
and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy.
During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to
NOLVADEX (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage
IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1
was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71,
respectively). Some patients received post-operative radiation therapy in addition to surgery.
Uterine sarcomas were reported in 4 women randomized to NOLVADEX (1 was FIGO IA, 1
was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and one patient randomized to placebo
(FIGO 1A); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients
randomized to NOLVADEX, the FIGO IA and IB cases were a MMMT and sarcoma,
respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the one patient
randomized to placebo had a MMMT. A similar increased incidence in endometrial
adenocarcinoma and uterine sarcoma was observed among women receiving NOLVADEX in
five other NSABP clinical trials.
Any patient receiving or who has previously received NOLVADEX who reports abnormal
vaginal bleeding should be promptly evaluated. Patients receiving or who have previously
received NOLVADEX should have annual gynecological examinations and they should
promptly inform their physicians if they experience any abnormal gynecological symptoms, eg,
menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain
or pressure.
In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate
compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5%
without sampling) for women with an intact uterus. There are no data to suggest that routine
endometrial sampling in asymptomatic women taking NOLVADEX to reduce the incidence of
breast cancer would be beneficial.
Non-Malignant Effects on the Uterus:
An increased incidence of endometrial changes including hyperplasia and polyps have been
reported in association with NOLVADEX treatment. The incidence and pattern of this increase
suggest that the underlying mechanism is related to the estrogenic properties of NOLVADEX.
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19
There have been a few reports of endometriosis and uterine fibroids in women receiving
NOLVADEX. The underlying mechanism may be due to the partial estrogenic effect of
NOLVADEX. Ovarian cysts have also been observed in a small number of premenopausal
patients with advanced breast cancer who have been treated with NOLVADEX.
NOLVADEX has been reported to cause menstrual irregularity or amenorrhea.
Thromboembolic Effects of NOLVADEX:
There is evidence of an increased incidence of thromboembolic events, including deep vein
thrombosis and pulmonary embolism, during NOLVADEX therapy. When NOLVADEX is
coadminstered with chemotherapy, there may be a further increase in the incidence of
thromboembolic effects. For treatment of breast cancer, the risks and benefits of NOLVADEX
should be carefully considered in women with a history of thromboembolic events.
Data from the NSABP P-1 trial show that participants receiving NOLVADEX without a history
of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-
NOLVADEX, 6-placebo, RR=3.01, 95% CI: 1.15- 9.27). Three of the pulmonary emboli, all in
the NOLVADEX arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism
occurred in women at least 50 years of age at randomization. Among women receiving
NOLVADEX, the events appeared between 2 and 60 months (average=27 months) from the start
of treatment.
In this same population, a non-statistically significant increase in deep vein thrombosis (DVT)
was seen in the NOLVADEX group (30-NOLVADEX, 19-placebo; RR=1.59, 95% CI: 0.86-
2.98). The same increase in relative risk was seen in women 49 and in women 50, although
fewer events occurred in younger women. Women with thromboembolic events were at risk for a
second related event (7 out of 25 women on placebo, 5 out of 48 women on NOLVADEX) and
were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on
NOLVADEX). Among women receiving NOLVADEX, deep vein thrombosis events occurred
between 2 and 57 months (average=19 months) from the start of treatment.
There was a non-statistically significant increase in stroke among patients randomized to
NOLVADEX (24-Placebo; 34-NOLVADEX; RR=1.42; 95% CI 0.82-2.51). Six of the 24 strokes
in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the
NOLVADEX group were categorized as hemorrhagic. Seventeen of the 34 strokes in the
NOLVADEX group were considered occlusive and 7 were considered to be of unknown
etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of
unknown etiology. Among these strokes 3 strokes in the placebo group and 4 strokes in the
NOLVADEX group were fatal. Eighty-eight percent of the strokes occurred in women at least 50
years of age at the time of randomization. Among women receiving NOLVADEX, the events
occurred between 1 and 63 months (average=30 months) from the start of treatment.
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Effects on the liver: Liver cancer:
In the Swedish trial using adjuvant NOLVADEX 40 mg/day for 2-5 years, 3 cases of liver cancer
have been reported in the NOLVADEX-treated group vs. 1 case in the observation group (See
PRECAUTIONS- Carcinogenesis). In other clinical trials evaluating NOLVADEX, no cases of
liver cancer have been reported to date.
One case of liver cancer was reported in NSABP P-1 in a participant randomized to
NOLVADEX.
Effects on the liver: Non-malignant effects:
NOLVADEX has been associated with changes in liver enzyme levels, and on rare occasions, a
spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and
hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the
relationship to NOLVADEX is uncertain. However, some positive rechallenges and
dechallenges have been reported.
In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin,
alkaline phosphatase) were observed (10 on placebo and 6 on NOLVADEX). Serum lipids were
not systematically collected.
Other cancers:
A number of second primary tumors, occurring at sites other than the endometrium, have been
reported following the treatment of breast cancer with NOLVADEX in clinical trials. Data from
the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients
receiving NOLVADEX. Whether an increased risk for other (non-uterine) cancers is associated
with NOLVADEX is still uncertain and continues to be evaluated.
Effects on the Eye:
Ocular disturbances, including corneal changes, decrement in color vision perception, retinal
vein thrombosis, and retinopathy have been reported in patients receiving NOLVADEX. An
increased incidence of cataracts and the need for cataract surgery have been reported in patients
receiving NOLVADEX.
In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts
among those women without cataracts at baseline (540-NOLVADEX; 483-placebo; RR=1.13,
95% CI: 1.00-1.28) was observed. Among these same women, NOLVADEX was associated
with an increased risk of having cataract surgery (101-NOLVADEX; 63-placebo; RR=1.62,
95% CI 1.18-2.22) (See Table 3 in CLINICAL PHARMACOLOGY). Among all women on
the trial (with or without cataracts at baseline), NOLVADEX was associated with an increased
risk of having cataract surgery (201-NOLVADEX; 129-placebo; RR=1.58, 95% CI 1.26-1.97).
Eye examinations were not required during the study. No other conclusions regarding non-
cataract ophthalmic events can be made.
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21
Pregnancy Category D:
NOLVADEX may cause fetal harm when administered to a pregnant woman. Women should be
advised not to become pregnant while taking NOLVADEX or within 2 months of discontinuing
NOLVADEX and should use barrier or nonhormonal contraceptive measures if sexually active.
Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on
reproductive functions are expected from the antiestrogenic properties of the drug. In
reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic
developmental skeletal changes were seen and were found reversible. In addition, in fertility
studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a
lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero
growth were observed, with slower learning behavior in some rat pups when compared to
historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2-fold the
daily maximum recommended human dose on a mg/m2 basis) during organogenesis or in the last
half of pregnancy. No deformations were seen and, although the dose was high enough to
terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of
teratogenic malformations.
In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4-fold
the daily maximum recommended human dose on a mg/m2 basis) caused changes in both sexes
that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the
clinical relevance of these changes is unknown, some of these changes, especially vaginal
adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in
utero and who have a 1 in 1000 risk of developing clear-cell adenocarcinoma of the vagina or
cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or
clear-cell adenocarcinoma of the vagina or cervix, in young women. However, only a small
number of young women have been exposed to tamoxifen in utero, and a smaller number have
been followed long enough (to age 15-20) to determine whether vaginal or cervical neoplasia
could occur as a result of this exposure.
There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have
been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and
fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes
pregnant while taking this drug, or within approximately two months after discontinuing therapy,
the patient should be apprised of the potential risks to the fetus including the potential long-term
risk of a DES-like syndrome.
Reduction in Breast Cancer Incidence in High Risk Women - Pregnancy Category
D:
For sexually active women of child-bearing potential, NOLVADEX therapy should be initiated
during menstruation. In women with menstrual irregularity, a negative B-HCG immediately
prior to the initiation of therapy is sufficient (See PRECAUTIONS-Information for Patients -
Reduction in Breast Cancer Incidence in High Risk Women).
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22
PRECAUTIONS
General:
Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been
occasionally reported in patients taking NOLVADEX for breast cancer. In patients with
significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if
these episodes are due to NOLVADEX therapy. Leukopenia has been observed, sometimes in
association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia
and pancytopenia in patients receiving NOLVADEX; this can sometimes be severe.
In the NSABP P-1 trial, 6 women on NOLVADEX and 2 on placebo experienced grade 3-4
drops in platelet counts (50,000/mm3).
Information for Patients:
Patients should be instructed to read the Medication Guide supplied as required by law when
NOLVADEX is dispensed. The complete text of the Medication Guide is reprinted at the end of
this document.
Reduction in Invasive Breast Cancer and DCIS in
Women with DCIS:
Women with DCIS treated with lumpectomy and radiation therapy who are considering
NOLVADEX to reduce the incidence of a second breast cancer event should assess the risks and
benefits of therapy, since treatment with NOLVADEX decreased the incidence of invasive breast
cancer, but has not been shown to affect survival (See Table 1 in CLINICAL
PHARMACOLOGY).
Reduction in Breast Cancer Incidence in High Risk Women:
Women who are at high risk for breast cancer can consider taking NOLVADEX therapy to
reduce the incidence of breast cancer. Whether the benefits of treatment are considered to
outweigh the risks depends on a woman’s personal health history and on how she weighs the
benefits and risks. NOLVADEX therapy to reduce the incidence of breast cancer may therefore
not be appropriate for all women at high risk for breast cancer. Women who are considering
NOLVADEX therapy should consult their health care professional for an assessment of the
potential benefits and risks prior to starting therapy for reduction in breast cancer incidence (See
Table 3 in CLINICAL PHARMACOLOGY). Women should understand that NOLVADEX
reduces the incidence of breast cancer, but may not eliminate risk. NOLVADEX decreased the
incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen
receptor negative tumors or larger tumors. In women with breast cancer who are at high risk of
developing a second breast cancer, treatment with about 5 years of NOLVADEX reduced the
annual incidence rate of a second breast cancer by approximately 50%.
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23
Women who are pregnant or who plan to become pregnant should not take NOLVADEX to
reduce her risk of breast cancer. Effective nonhormonal contraception must be used by all
premenopausal women taking NOLVADEX and for approximately two months after
discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in
the presence of menstrual irregularity. For sexually active women of child-bearing potential,
NOLVADEX therapy should be initiated during menstruation. In women with menstrual
irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient (See
WARNINGS-Pregnancy Category D).
Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed
no difference in the number of breast cancer cases between the tamoxifen and placebo arms.
These studies had trial designs that differed from that of NSABP P-1, were smaller than NSABP
P-1, and enrolled women at a lower risk for breast cancer than those in P-1.
Monitoring During NOLVADEX Therapy:
Women taking or having previously taken NOLVADEX should be instructed to seek prompt
medical attention for new breast lumps, vaginal bleeding, gynecologic symptoms (menstrual
irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of leg swelling
or tenderness, unexplained shortness of breath, or changes in vision. Women should inform all
care providers, regardless of the reason for evaluation, that they take NOLVADEX.
Women taking NOLVADEX to reduce the incidence of breast cancer should have a breast
examination, a mammogram, and a gynecologic examination prior to the initiation of therapy.
These studies should be repeated at regular intervals while on therapy, in keeping with good
medical practice. Women taking NOLVADEX as adjuvant breast cancer therapy should follow
the same monitoring procedures as for women taking NOLVADEX for the reduction in the
incidence of breast cancer. Women taking NOLVADEX as treatment for metastatic breast
cancer should review this monitoring plan with their care provider and select the appropriate
modalities and schedule of evaluation.
Laboratory Tests:
Periodic complete blood counts, including platelet counts, and periodic liver function tests
should be obtained.
Drug Interactions:
When NOLVADEX is used in combination with coumarin-type anticoagulants, a significant
increase in anticoagulant effect may occur. Where such coadministration exists, careful
monitoring of the patient’s prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were
ineligible for participation in the trial (See CONTRAINDICATIONS).
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in
combination with NOLVADEX.
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24
Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on
metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other
drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-
desmethyl tamoxifen plasma concentrations have been shown to be reduced when
coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated
metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4
inducing agents have not been studied to confirm this effect.
One patient receiving NOLVADEX with concomitant phenobarbital exhibited a steady state
serum level of tamoxifen lower than that observed for other patients (ie, 26 ng/mL vs. mean
value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin
induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of
tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen
plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but
not tamoxifen.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-
desmethyl tamoxifen.
Drug/Laboratory Testing Interactions:
During postmarketing surveillance, T4 elevations were reported for a few postmenopausal
patients which may be explained by increases in thyroid-binding globulin. These elevations
were not accompanied by clinical hyperthyroidism.
Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect
on Pap smears have been infrequently seen in postmenopausal patients given NOLVADEX.
In the postmarketing experience with NOLVADEX, infrequent cases of hyperlipidemias have
been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in
patients with pre-existing hyperlipidemias (See ADVERSE REACTIONS-Postmarketing
experience section).
Carcinogenesis:
A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three
and seven-fold the daily maximum recommended human dose on a mg/m2 basis) administered by
oral gavage for up to 2 years) revealed a significant increase in hepatocellular carcinoma at all
doses. The incidence of these tumors was significantly greater among rats administered 20 or
35 mg/kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study,
rats were administered tamoxifen at 45 mg/kg/day (about nine-fold the daily maximum
recommended human dose on a mg/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6
months.
Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two
separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen
for 13 to 15 months at doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the
daily recommended human dose on a mg/m2 basis).
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Mutagenesis:
No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro-
and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA
adducts were observed by 32P post-labeling in DNA from rat liver and cultured human
lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in
vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is
genotoxic in rodent and human MCL-5 cells.
Impairment of Fertility:
Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04
mg/kg/day (about 0.01-fold the daily maximum recommended human dose on a mg/m2 basis)
when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and
reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also
increased at doses of 0.16 mg/kg/day (about 0.03-fold the daily maximum recommended human
dose on a mg/m2 basis) when female rats were dosed from days 7-17 of pregnancy. Tamoxifen
produced abortion, premature delivery and fetal death in rabbits administered doses equal to or
greater than 0.125 mg/kg/day (about 0.05-fold the daily maximum recommended human dose on
a mg/m2 basis). There were no teratogenic changes in either rats or rabbits.
Pregnancy Category D:
See WARNINGS.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions in nursing infants from
NOLVADEX, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use:
The safety and efficacy of NOLVADEX for girls aged two to 10 years with McCune-
Albright Syndrome and precocious puberty have not been studied beyond one year of
treatment. The long-term effects of NOLVADEX therapy for girls have not been
established. In adults treated with NOLVADEX, an increase in incidence of uterine
malignancies, stroke and pulmonary embolism has been noted (see BOXED WARNING, and
CLINICAL PHARMACOLOGY-Clinical Studies-McCune-Albright Syndrome subsection).
Geriatric Use:
In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at
least 70 years of age accounted for 6% of the participants. A reduction in breast cancer
incidence was seen among participants in each of the subsets: A total of 28 and 10 invasive
breast cancers were seen among participants 65 and older in the placebo and NOLVADEX
groups, respectively. Across all other outcomes, the results in this subset reflect the results
observed in the subset of women at least 50 years of age. No overall differences in tolerability
were observed between older and younger patients (See CLINICAL PHARMACOLOGY -
Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women section).
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In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at
least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast
cancers were seen among participants 65 and older in the placebo and NOLVADEX groups,
respectively. This subset is too small to reach any conclusions on efficacy. Across all other
endpoints, the results in this subset were comparable to those of younger women enrolled in this
trial. No overall differences in tolerability were observed between older and younger patients.
ADVERSE REACTIONS
Adverse reactions to NOLVADEX are relatively mild and rarely severe enough to require
discontinuation of treatment in breast cancer patients.
Continued clinical studies have resulted in further information which better indicates the
incidence of adverse reactions with NOLVADEX as compared to placebo.
Metastatic Breast Cancer:
Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes
associated with a good tumor response. Patients with increased bone pain may require additional
analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting
lesions, sometimes associated with marked erythema within and surrounding the lesions and/or
the development of new lesions. When they occur, the bone pain or disease flare are seen shortly
after starting NOLVADEX and generally subside rapidly.
In patients treated with NOLVADEX for metastatic breast cancer, the most frequent adverse
reaction to NOLVADEX is hot flashes.
Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema,
distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair
thinning and/or partial hair loss, and vaginal dryness.
Premenopausal Women:
The following table summarizes the incidence of adverse reactions reported at a frequency of 2%
or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared NOLVADEX
therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.
Adverse Reactions*
NOLVADEX
All Effects
% of Women
n=104
OVARIAN
ABLATION
All Effects
% of Women
n=100
Flush
33
46
Amenorrhea
16
69
Altered Menses
13
5
Oligomenorrhea
9
1
Bone Pain
6
6
Menstrual Disorder
6
4
Nausea
5
4
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Cough/Coughing
4
1
Edema
4
1
Fatigue
4
1
Muscoloskeletal Pain
3
0
Pain
3
4
Ovarian Cyst(s)
3
2
Depression
2
2
Abdominal Cramps
1
2
Anorexia
1
2
*Some women had more than one adverse reaction.
Male Breast Cancer:
NOLVADEX is well tolerated in males with breast cancer. Reports from the literature and case
reports suggest that the safety profile of NOLVADEX in males is similar to that seen in women.
Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male
patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and
estrogen levels were elevated. No significant clinical changes were reported.
Adjuvant Breast Cancer:
In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to
5 years of NOLVADEX 20 mg/day or placebo following primary surgery. The reported adverse
effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse events
more common on NOLVADEX than on placebo. The incidence of hot flashes (64% vs. 48%),
vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with
NOLVADEX compared with placebo. All other adverse effects occurred with similar frequency
in the 2 treatment groups, with the exception of thrombotic events; a higher incidence was seen
in NOLVADEX-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated
with NOLVADEX who had thrombotic events died.
NSABP B-14 Study
% of Women
Adverse Effect
NOLVADEX
(n=1422)
Placebo
(n=1437)
Hot Flashes
64
48
Fluid Retention
32
30
Vaginal Discharge
30
15
Nausea
26
24
Irregular Menses
25
19
Weight Loss (>5%)
23
18
Skin Changes
19
15
Increased SGOT
5
3
Increased Bilirubin
2
1
Increased Creatinine
2
1
Thrombocytopenia*
2
1
Thrombotic Events
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Deep Vein Thrombosis
0.8
0.2
Pulmonary Embolism
0.5
0.2
Superficial Phlebitis
0.4
0.0
*Defined as a platelet count of <100,000/mm3
In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, NOLVADEX
or placebo was administered for 2 years to women following mastectomy. When compared to
placebo, NOLVADEX showed a significantly higher incidence of hot flashes (19% vs. 8% for
placebo). The incidence of all other adverse reactions was similar in the 2 treatment groups with
the exception of thrombocytopenia where the incidence for NOLVADEX was 10% vs. 3% for
placebo, an observation of borderline statistical significance.
In other adjuvant studies, Toronto and NOLVADEX Adjuvant Trial Organization (NATO),
women received either NOLVADEX or no therapy. In the Toronto study, hot flashes were
observed in 29% of patients for NOLVADEX vs. 1% in the untreated group. In the NATO trial,
hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for
NOLVADEX vs. 0.2% for each in the untreated group.
Ductal Carcinoma in Situ (DCIS):
The type and frequency of adverse events in the NSABP B-24 trial were consistent with those
observed in the other adjuvant trials conducted with NOLVADEX.
Reduction in Breast Cancer Incidence in High Risk Women:
In the NSABP P-1 Trial, there was an increase in five serious adverse effects in the
NOLVADEX group: endometrial cancer (33 cases in the NOLVADEX group vs. 14 in the
placebo group); pulmonary embolism (18 cases in the NOLVADEX group vs. 6 in the placebo
group); deep vein thrombosis (30 cases in the NOLVADEX group vs. 19 in the placebo group);
stroke (34 cases in the NOLVADEX group vs. 24 in the placebo group); cataract formation (540
cases in the NOLVADEX group vs. 483 in the placebo group) and cataract surgery (101 cases in
the NOLVADEX group vs. 63 in the placebo group) (See WARNINGS and Table 3 in
CLINICAL PHARMACOLOGY).
The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only
adverse events more common on NOLVADEX than placebo are shown.
NSABP P-1 Trial: All Adverse Events
% of Women
NOLVADEX
N=6681
PLACEBO
N=6707)
Self Reported Symptoms
N=64411
N=64691
Hot Flashes
80
68
Vaginal Discharges
55
35
Vaginal Bleeding
23
22
Laboratory Abnormalities
N=65202
N=65352
Platelets decreased
0.7
0.3
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Adverse Effects
N=64923
N=64843
Other Toxicities
Mood
11.6
10.8
Infection/Sepsis
6.0
5.1
Constipation
4.4
3.2
Alopecia
5.2
4.4
Skin
5.6
4.7
Allergy
2.5
2.1
1Number with Quality of Life Questionnaires
2Number with Treatment Follow-up Forms
3Number with Adverse Drug Reaction Forms
In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving NOLVADEX and placebo
therapy, respectively withdrew from the trial for medical reasons. The following are the medical
reasons for withdrawing from NOLVADEX and placebo therapy, respectively: Hot flashes
(3.1% vs. 1.5%) and Vaginal Discharge (0.5% vs. 0.1%).
In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving NOLVADEX and placebo
therapy, respectively withdrew for non-medical reasons.
On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and
in 80% of women on NOLVADEX. Severe hot flashes occurred in 28% of women on placebo
and 45% of women on NOLVADEX. Vaginal discharge occurred in 35% and 55% of women
on placebo and NOLVADEX respectively; and was severe in 4.5% and 12.3% respectively.
There was no difference in the incidence of vaginal bleeding between treatment arms.
Pediatric Patients - McCune-Albright Syndrome:
Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-
year study. A causal relationship has not been established; however, as an increase in the
incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated
with NOLVADEX (see BOXED WARNING), continued monitoring of McCune-Albright
patients treated with NOLVADEX for long-term effects is recommended. The safety and
efficacy of NOLVADEX for girls aged two to 10 years with McCune-Albright Syndrome
and precocious puberty have not been studied beyond one year to treatment. The long-
term effects of NOLVADEX therapy in girls have not been established.
Postmarketing experience:
Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual
irregularities, skin rash and headaches. Usually these have not been of sufficient severity to
require dosage reduction or discontinuation of treatment. Very rare reports of erythema
multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare
reports of hypersensitivity reactions including angioedema have been reported with
NOLVADEX therapy. In some of these cases, the time to onset was more than one year.
Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated
with the use of NOLVADEX (see PRECAUTIONS- Drug/Laboratory Testing Interactions
section).
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OVERDOSAGE
Signs observed at the highest doses following studies to determine LD50 in animals were
respiratory difficulties and convulsions.
Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer
patients which specifically determined the maximum tolerated dose of NOLVADEX in
evaluating the use of very high doses to reverse multidrug resistance, acute neurotoxicity
manifested by tremor, hyperreflexia, unsteady gait and dizziness were noted. These symptoms
occurred within 3-5 days of beginning NOLVADEX and cleared within 2-5 days after stopping
therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several
days after NOLVADEX was discontinued and neurotoxic symptoms had resolved. The causal
relationship of the seizure to NOLVADEX therapy is unknown. Doses given in these patients
were all greater than 400 mg/m2 loading dose, followed by maintenance doses of 150 mg/m2 of
NOLVADEX given twice a day.
In the same study, prolongation of the QT interval on the electrocardiogram was noted when
patients were given doses higher than 250 mg/m2 loading dose, followed by maintenance doses
of 80 mg/m2 of NOLVADEX given twice a day. For a woman with a body surface area of
1.5 m2 the minimal loading dose and maintenance doses given at which neurological symptoms
and QT changes occurred were at least 6 fold higher in respect to the maximum recommended
dose.
No specific treatment for overdosage is known; treatment must be symptomatic.
DOSAGE AND ADMINISTRATION
For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than
20 mg per day should be given in divided doses (morning and evening).
In three single agent adjuvant studies in women, one 10 mg NOLVADEX tablet was
administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the
NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg
NOLVADEX tablet was given twice a day for at least 5 years. Results of the B-14 study suggest
that continuation of therapy beyond five years does not provide additional benefit (see
CLINICAL PHARMACOLOGY). In the EBCTCG 1995 overview, the reduction in recurrence
and mortality was greater in those studies that used tamoxifen for about 5 years than in those that
used tamoxifen for a shorter period of therapy. There was no indication that doses greater than
20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant
NOLVADEX therapy for patients with breast cancer.
Ductal Carcinoma in Situ (DCIS):
The recommended dose is NOLVADEX 20 mg daily for 5 years.
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Reduction in Breast Cancer Incidence in High Risk Women:
The recommended dose is NOLVADEX 20 mg daily for 5 years. There are no data to support
the use of NOLVADEX other than for 5 years (See CLINICAL PHARMACOLOGY-Clinical
Studies - Reduction in Breast Cancer Incidence in High Risk Women).
HOW SUPPLIED
10 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 10 mg of
tamoxifen (round, biconvex, uncoated, white tablet identified with NOLVADEX 600 debossed
on one side and a cameo debossed on the other side) are supplied in bottles of 60 tablets. NDC
0310-0600.
20 mg Tablets containing tamoxifen as the citrate in an amount equivalent to 20 mg of
tamoxifen (round, biconvex, uncoated, white tablet identified with NOLVADEX 604 debossed
on one side and a cameo debossed on the other side) are supplied in bottles of 30 tablets. NDC
0310-0604.
Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in a well-closed,
light-resistant container.
MEDICATION GUIDE
NOLVADEX· (NOLE-vah-dex) Tablets
Generic name: tamoxifen (ta-MOX-I-fen)
Written for women who use NOLVADEX to lower their high chance of getting breast cancer or
who have ductal carcinoma in situ (DCIS)
This Medication Guide discusses only the use of NOLVADEX to lower the chance of getting
breast cancer in high-risk women and in women treated for DCIS.
People taking NOLVADEX to treat breast cancer have different benefits and different decisions
to make than high-risk women or women with ductal carcinoma in situ (DCIS) taking
NOLVADEX to reduce the chance of getting breast cancer. If you already have breast cancer,
talk with your doctor about how the benefits of treating breast cancer with NOLVADEX
compare to the risks that are described in this document.
Why should I read this Medication Guide?
This guide has information to help you decide whether to use NOLVADEX to lower your chance
of getting breast cancer.
You and your doctor should talk about whether the possible benefit of NOLVADEX in
lowering your high chance of getting breast cancer is greater than its possible risks. Your
doctor has a special computer program or hand-held calculator to tell if you are in the high-risk
group. If you have DCIS and have been treated with surgery and radiation therapy, your doctor
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32
may prescribe NOLVADEX to decrease your chance of getting invasive (spreading) breast
cancer.
Read this guide carefully before you start NOLVADEX. It is important to read the information
you get each time you get more medicine. There may be something new. This guide does not
tell you everything about NOLVADEX and does not take the place of talking with your doctor.
Only you and your doctor can determine if NOLVADEX is right for you.
What is the most important information I should know about using
NOLVADEX to reduce the chance of getting breast cancer?
NOLVADEX is a prescription medicine that is like estrogen (female hormone) in some ways and
different in other ways. In the breast, NOLVADEX can block estrogen’s effects. Because it
does this, NOLVADEX may block the growth of breast cancers that need estrogen to grow
(cancers that are estrogen- or progesterone-receptor positive).
NOLVADEX can lower the chance of getting breast cancer in women with a higher than normal
chance of getting breast cancer in the next five years (high-risk women) and women with DCIS.
Because high-risk women don’t have cancer yet, it is important to think carefully about
whether the possible benefit of NOLVADEX in lowering the chance of getting breast
cancer is greater than its possible risks.
This Medication Guide reviews the risks and benefits of using NOLVADEX to reduce the
chance of getting breast cancer in high-risk women and women with DCIS. This guide does not
discuss the special benefits and decisions for people who already have breast cancer.
Why do women and men use NOLVADEX?
NOLVADEX has more than one use. NOLVADEX is used:
to lower the chance of getting breast cancer in women with a higher than normal chance of
getting breast cancer in the next 5 years (high-risk women)
to lower the chance of getting invasive (spreading) breast cancer in women who had surgery
and radiation for ductal carcinoma in situ (DCIS). DCIS means the cancer is only inside the milk
ducts.
to treat breast cancer in women after they have finished early treatment. Early treatment can
include surgery, radiation, and chemotherapy. NOLVADEX may keep the cancer from
spreading to others parts of the body. It may also reduce the woman’s chance of getting a new
breast cancer.
in women and men, to treat breast cancer that has spread to other parts of the body (metastatic
breast cancer).
This guide talks only about using NOLVADEX to lower the chance of getting breast cancer (#1
and #2 above).
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What are the benefits of NOLVADEX to lower the chance of getting breast
cancer in high-risk women and in women treated for DCIS?
A large US study looked at high-risk women and compared the ones who took NOLVADEX for
5 years with others who took a pill without NOLVADEX (placebo). High-risk women were
defined as women who have a 1.7% or greater chance of getting breast cancer in the next 5 years,
based on a special computer program. In this study:
Out of every 1,000 high-risk women who took a placebo, each year about 7 got breast
cancer.
Out of every 1,000 high-risk women who took NOLVADEX, each year about 4 got
breast cancer.
The study showed that on average, high-risk women who took NOLVADEX lowered their
chances of getting breast cancer by 44%, from 7 in 1,000 to 4 in 1,000.
Another US study looked at women with DCIS and compared those who took NOLVADEX for
5 years with others who took a placebo. In this study:
Out of every 1,000 women with DCIS who took placebo, each year about 17 got breast
cancer.
Out of every 1,000 women with DCIS who took NOLVADEX, each year about 10 got
breast cancer.
The study showed that on average, women with DCIS who took NOLVADEX lowered their
chances of getting invasive (spreading) breast cancer by 43%, from 17 in 1,000 to 10 in 1,000.
These studies do not mean that taking NOLVADEX will lower your personal chance of
getting breast cancer. We do not know what the benefits will be for any one woman who takes
NOLVADEX to reduce her chance of getting breast cancer.
What are the risks of NOLVADEX?
In the studies described under “What are the benefits of NOLVADEX?”, the high-risk women
who took NOLVADEX got certain side effects at a higher rate than those who took a placebo.
Some of these side effects can cause death.
In one study, in women who still had their uterus
Out of every 1,000 women who took a placebo, each year 1 got endometrial cancer
(cancer of the lining of the uterus) and none got uterine sarcoma (cancer of the body of
the uterus).
Out of every 1,000 women who took NOLVADEX, each year 2 got endometrial cancer
and fewer than 1 got uterine sarcoma.
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These results show that, on average, in high-risk women who still had their uterus,
NOLVADEX doubled the chance of getting endometrial cancer from 1 in 1,000 to 2 in 1,000,
and it increased the chance of getting uterine sarcoma. This does not mean that taking
NOLVADEX will double your personal chance of getting endometrial cancer or increase
your chance of getting uterine sarcoma. We do not know what this risk will be for any one
woman. The risk is different for women who no longer have their uterus.
For all women in this study, taking NOLVADEX increased the risk of having a blood clot
in their lungs or veins, or of having a stroke. In some cases, women died from these effects.
NOLVADEX increased the risk of getting cataracts (clouding of the lens of the eye) or
needing cataract surgery. (See “What are the possible side effects of NOLVADEX?” for more
details about side effects.)
What don’t we know about taking NOLVADEX to reduce the chance of
getting breast cancer?
We don’t know
if NOLVADEX lowers the chance of getting breast cancer in women who have abnormal
breast cancer genes (BRCA1 and BRCA2)
if taking NOLVADEX for 5 years reduces the number of breast cancers a woman will get
in her lifetime or if it only delays some breast cancers
if NOLVADEX helps a woman live longer
the effects of taking NOLVADEX with hormone replacement therapy (HRT), birth
control pills, or androgens (male hormones)
the benefits of taking NOLVADEX if you are less than 35 years old
Studies are being done to learn more about the long-term benefits and risks of using
NOLVADEX to reduce the chance of getting breast cancer.
What are the possible side effects of NOLVADEX?
The most common side effect of NOLVADEX is hot flashes. This is not a sign of a serious
problem.
The next most common side effect is vaginal discharge. If the discharge is bloody, it could be a
sign of a serious problem. [See “Changes in the lining (endometrium) or body of your uterus”
below.]
Less common but serious side effects of NOLVADEX are listed below. These can occur at any
time. Call your doctor right away if you have any signs of side effects listed below:
Changes in the lining (endometrium) or body of your uterus. These changes may
mean serious problems are starting, including cancer of the uterus. The signs of changes
in the uterus are:
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35
- Vaginal bleeding or bloody discharge that could be a rusty or brown color. You should
call your doctor even if only a small amount of bleeding occurs.
- Change in your monthly bleeding, such as in the amount or timing of bleeding or
increased clotting.
- Pain or pressure in your pelvis (below your belly button).
Blood clots in your veins or lungs. These can cause serious problems, including death.
You may get clots up to 2-3 months after you stop taking NOLVADEX. The signs of
blood clots are:
- sudden chest pain, shortness of breath, coughing up blood
- pain, tenderness, or swelling in one or both of your legs
Stroke. Stroke can cause serious medical problems, including death. The signs of stroke
are:
- sudden weakness, tingling, or numbness in your face, arm or leg, especially on one
side of your body
- sudden confusion, trouble speaking or understanding
- sudden trouble seeing in one or both eyes
- sudden trouble walking, dizziness, loss of balance or coordination
- sudden severe headache with no known cause
Cataracts or increased chance of needing cataract surgery. The sign of these
problems is slow blurring of your vision.
Liver problems, including jaundice. The signs of liver problems include lack of
appetite and yellowing of your skin or whites of your eyes.
These are not all the possible side effects of NOLVADEX. For a complete list, ask your doctor
or pharmacist.
Who should not take NOLVADEX?
Do not take NOLVADEX for any reason if you
Are pregnant or plan to become pregnant while taking NOLVADEX or during the 2
months after you stop taking NOLVADEX. NOLVADEX may harm your unborn
baby. It takes about 2 months to clear NOLVADEX from your body. To be sure you are
not pregnant, you can start taking NOLVADEX while you are having your menstrual
period. Or, you can take a pregnancy test to be sure you are not pregnant before you
begin.
Are breast feeding. We do not know if NOLVADEX can pass through your milk and
harm your baby.
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36
Have had an allergic reaction to NOLVADEX or tamoxifen (the other name for
NOLVADEX), or to any of its inactive ingredients.
If you get pregnant while taking NOLVADEX, stop taking it right away and contact your
doctor. NOLVADEX may harm your unborn baby.
Do not take NOLVADEX to lower your chance of getting breast cancer if
You ever had a blood clot that needed medical treatment.
You are taking medicines to thin your blood, like warfarin, (also called Coumadin®*).
Your ability to move around is limited for most of your waking hours.
You are at risk for blood clots. Your doctor can tell you if you are at high risk for blood
clots.
You do not have a higher than normal chance of getting breast cancer. Your doctor can
tell you if you are a high-risk woman.
How should I take NOLVADEX?
Swallow the tablet(s) whole, with water or another non-alcoholic liquid. You can take
NOLVADEX with or without food. Take your medicine every day. It may be easier to
remember if you take it at the same time each day.
If you forget a dose, take it when you remember, then take the next dose as usual. If it is
almost time for your next dose or you remember at your next dose, do not take extra
tablets to make up the missed dose.
Take NOLVADEX for 5 years, unless your doctor tells you otherwise.
What should I avoid while taking NOLVADEX?
Do not become pregnant while taking NOLVADEX or for 2 months after you stop.
NOLVADEX can stop hormonal birth control methods from working. Hormonal
methods include birth control pills, patches, injections, rings and implants. Therefore,
while taking NOLVADEX, use birth control methods that don’t use hormones, such
as condoms, diaphragms with spermicide, or plain IUD’s. If you get pregnant, stop
taking NOLVADEX right away and call your doctor.
Do not breast feed. We do not know if NOLVADEX can pass through your milk and if
it can harm the baby.
What should I do while taking NOLVADEX?
Have regular gynecology check-ups (“female exams”), breast exams and mammograms.
Your doctor will tell you how often. These will check for signs of breast cancer and
cancer of the endometrium (lining of the uterus). Because NOLVADEX does not prevent
all breast cancers, and you may get other types of cancers, you need these exams to find
any cancers as early as possible.
Because NOLVADEX can cause serious side effects, pay close attention to your body.
Signs you should look for are listed in “What are the possible side effects of
NOLVADEX?”
Tell all of the doctors that you see that you are taking NOLVADEX.
Tell your doctor right away if you have any new breast lumps.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
General information about the safe and effective use of NOLVADEX
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Your doctor has prescribed NOLVADEX only for you. Do not give it to other people, even if
they have a similar condition, because it may harm them. Do not use it for a condition for which
it was not prescribed.
This Medication Guide is a summary of information about NOLVADEX for women who use
NOLVADEX to lower their high chance of getting breast cancer or who have DCIS. If you want
more information about NOLVADEX, ask your doctor or pharmacist. They can give you
information about NOLVADEX that is written for health professionals. For more information
about NOLVADEX or breast cancer, please visit www.NOLVADEX.com or call 1-800-236-
9933.
Ingredients: tamoxifen citrate, carboxymethylcellulose calcium, magnesium stearate, mannitol
and starch.
*Coumadin· is a registered trademark of Bristol-Myers Squibb Pharmaceuticals.
All other trademarks are the property of the AstraZeneca group
AstraZeneca Pharmaceuticals LP
Wilmington, Delaware 19850-5437
Rev 04-15-04 SIC XXXXX-XXPrinted in USA ¸2003 AstraZeneca
This Medication Guide has been approved by the US Food and Drug Administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Attachment 1
Page 1
Class Suicidality Labeling Language for Antidepressants
[This section should be located at the beginning of the package insert with bolded font and
enclosed in a black box]
[Insert established name]
Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term
studies in children and adolescents with Major Depressive Disorder (MDD) and other
psychiatric disorders. Anyone considering the use of [Insert established name] or any other
antidepressant in a child or adolescent must balance this risk with the clinical need. Patients
who are started on therapy should be observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. [Insert established name] is not approved
for use in pediatric patients. (See Warnings and Precautions: Pediatric Use)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs
(SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive
compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over
4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or
behavior (suicidality) during the first few months of treatment in those receiving
antidepressants. The average risk of such events in patients receiving antidepressants was 4%,
twice the placebo risk of 2%. No suicides occurred in these trials.
[This section should be located under WARNINGS. Please note that the title of this
section should be bolded, and it should be the first paragraph in this section.]
WARNINGS-Clinical Worsening and Suicide Risk
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. There has been a long-standing concern that antidepressants
may have a role in inducing worsening of depression and the emergence of suicidality in certain
patients. A causal role for antidepressants in inducing suicidality has been established in pediatric
patients.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in
children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving
over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or
thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The
average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 1
Page 2
There was considerable variation in risk among drugs, but a tendency toward an increase for almost
all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there
were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive
disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is
unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond
several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes, either increases or
decreases. Such observation would generally include at least weekly face-to-face contact with
patients or their family members or caregivers during the first 4 weeks of treatment, then every
other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12
weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being
treated with antidepressants should be observed similarly for clinical worsening and suicidality,
especially during the initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adult and pediatric patients being treated with antidepressants for major depressive disorder
as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between
the emergence of such symptoms and either the worsening of depression and/or the emergence of
suicidal impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of pediatric patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted
about the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality, and
to report such symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for [Insert established name] should be
written for the smallest quantity of tablets consistent with good patient management, in order to reduce
the risk of overdose. Families and caregivers of adults being treated for depression should be similarly
advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled trials) that treating
such an episode with an antidepressant alone may increase the likelihood of precipitation of a
mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 1
Page 3
above represent such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a
family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established
name] is not approved for use in treating bipolar depression.
[This section should be located under PRECAUTIONS, Information for Patients.]
Prescribers or other health professionals should inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with [Insert established name] and should
counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in
Children and Adolescents is available for [Insert established name]. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication Guide
and should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur
while taking [Insert established name].
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual
changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant
treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised
to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
symptoms should be reported to the patient's prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be
associated with an increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
[This section should be located under PRECAUTIONS, Pediatric Use.]
Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX
WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of
[Insert established name] in a child or adolescent must balance the potential risks with the clinical
need.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 1
Medication Guide
About Using Antidepressants in Children and Teenagers
What is the most important information I should know if my child is being prescribed an
antidepressant?
Parents or guardians need to think about 4 important things when their child is prescribed an
antidepressant:
1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants
1. There is a Risk of Suicidal Thoughts or Actions
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal
thoughts and actions can also be caused by depression, a serious medical condition that is commonly
treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called
suicidality or being suicidal.
A large study combined the results of 24 different studies of children and teenagers with depression or
other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to
4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar
pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became
suicidal.
For some children and teenagers, the risks of suicidal actions may be especially high. These
include patients with
• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide
If any of these are present, make sure you tell your healthcare provider before your child takes an
antidepressant.
2. How to Try to Prevent Suicidal Thoughts and Actions
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or
his moods or actions, especially if the changes occur suddenly. Other important people in your child's
life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other
important people). The changes to look out for are listed in Section 3, on what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 2
After starting an antidepressant, your child should generally see his or her healthcare provider:
• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider's advice about how often to come back
• More often if problems or questions arise (see other side)
You should call your child's healthcare provider between visits if needed.
3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant
Contact your child's healthcare provider right away if your child exhibits any of the following signs for
the first time, or if they seem worse, or worry you, your child, or your child's teacher:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood
Never let your child stop taking an antidepressant without first talking to his or her healthcare
provider. Stopping an antidepressant suddenly can cause other symptoms.
4. There are Benefits and Risks When Using Antidepressants
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can
lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal
thinking or actions. It is important to discuss all the risks of treating depression and also the risks of
not treating it. You and your child should discuss all treatment choices with your healthcare provider,
not just the use of antidepressants.
Other side effects can occur with antidepressants (see section below).
Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric
depression.
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
(ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) .
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 3
Your healthcare provider may suggest other antidepressants based on the past experience of your child
or other family members.
Is this all I need to know if my child is being prescribed an antidepressant?
No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants.
Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is
prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare
provider or pharmacist where to find more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Pamelor™
(nortriptyline HCl) capsules USP
(nortriptyline HCl) oral solution USP
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term
studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of nortriptyline hydrochloride or any other
antidepressant in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24;
there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately
and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Nortriptyline hydrochloride
is not approved for use in pediatric patients (see WARNINGS, Clinical Worsening
and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS,
Pediatric Use).
DESCRIPTION
Pamelor™
(nortriptyline
HCl)
is
1-propanamine,
3-(10,11-dihydro-5H
dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-, hydrochloride.
The structural formula is as follows: structural formula
C19H21N•HCl
MW = 299.84
10 mg, 25 mg, 50 mg, and 75 mg Capsules
Active Ingredient: nortriptyline hydrochloride USP.
Page 1 of 15
10_2012.2
Reference ID: 3209061
10 mg, 25 mg, and 75 mg Capsules
Inactive Ingredients: D&C Yellow #10, FD&C Yellow #6, gelatin, silicone fluid, starch,
and titanium dioxide.
50 mg Capsules
Inactive Ingredients: gelatin, silicone fluid, starch, and titanium dioxide.
Solution
Active Ingredient: nortriptyline hydrochloride USP.
Inactive Ingredients: alcohol, benzoic acid, flavoring, purified water, and sorbitol.
CLINICAL PHARMACOLOGY
The mechanism of mood elevation by tricyclic antidepressants is at present unknown.
Pamelor is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse
agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor
effect of norepinephrine but blocks the pressor response of phenethylamine. Studies
suggest that Pamelor interferes with the transport, release, and storage of
catecholamines. Operant conditioning techniques in rats and pigeons suggest that
Pamelor has a combination of stimulant and depressant properties.
INDICATIONS AND USAGE
Pamelor™ (nortriptyline HCl) is indicated for the relief of symptoms of depression.
Endogenous depressions are more likely to be alleviated than are other depressive
states.
CONTRAINDICATIONS
Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with Pamelor or within 14 days
of stopping treatment with Pamelor is contraindicated because of an increased risk of
serotonin syndrome. The use of Pamelor within 14 days of stopping an MAOI intended
to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE
AND ADMINISTRATION).
Starting Pamelor in a patient who is being treated with MAOIs such as linezolid or
intravenous methylene blue is also contraindicated because of an increased risk of
serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Hypersensitivity to Tricyclic Antidepressants
Cross-sensitivity between Pamelor and other dibenzazepines is a possibility.
Myocardial Infarction
Pamelor is contraindicated during the acute recovery period after myocardial infarction.
Page 2 of 15
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Reference ID: 3209061
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation and
behavior (suicidality) or unusual changes in behavior, whether or not they are taking
antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-
standing concern, however, that antidepressants may have a role in inducing worsening
of depression and the emergence of suicidality in certain patients during the early
phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
(ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction
with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders
included a total of 295 short-term trials (median duration of 2 months) of 11
antidepressant drugs in over 77,000 patients. There was considerable variation in risk of
suicidality among drugs, but a tendency toward an increase in the younger patients for
almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per
1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Increases Compared to Placebo
<18
18-24
14 additional cases
5 additional cases
Decreases Compared to Placebo
25-64
≥65
1 fewer case
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
Page 3 of 15
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Reference ID: 3209061
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond
several months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants can delay
the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of a
course of drug therapy, or at times of dose changes, either increases or
decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and
mania, have been reported in adult and pediatric patients being treated with
antidepressants for major depressive disorder as well as for other indications, both
psychiatric and nonpsychiatric. Although a causal link between the emergence of such
symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who
are experiencing emergent suicidality or symptoms that might be precursors to
worsening depression or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of
agitation, irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report such
symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for nortriptyline
hydrochloride should be written for the smallest quantity of capsules consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder – A major depressive episode may be the
initial presentation of bipolar disorder. It is generally believed (though not established in
controlled trials) that treating such an episode with an antidepressant alone may
increase the likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an antidepressant,
patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that nortriptyline hydrochloride is not approved for use in treating bipolar
depression.
Page 4 of 15
10_2012.2
Reference ID: 3209061
Patients with cardiovascular disease should be given Pamelor only under close
supervision because of the tendency of the drug to produce sinus tachycardia and to
prolong the conduction time. Myocardial infarction, arrhythmia, and strokes have
occurred. The antihypertensive action of guanethidine and similar agents may be
blocked. Because of its anticholinergic activity, Pamelor should be used with great
caution in patients who have glaucoma or a history of urinary retention. Patients with a
history of seizures should be followed closely when Pamelor is administered, inasmuch
as this drug is known to lower the convulsive threshold. Great care is required if
Pamelor is given to hyperthyroid patients or to those receiving thyroid medication, since
cardiac arrhythmias may develop.
Pamelor may impair the mental and/or physical abilities required for the performance of
hazardous tasks, such as operating machinery or driving a car; therefore, the patient
should be warned accordingly.
Excessive consumption of alcohol in combination with nortriptyline therapy may have a
potentiating effect, which may lead to the danger of increased suicidal attempts or
overdosage, especially in patients with histories of emotional disturbances or suicidal
ideation.
The concomitant administration of quinidine and nortriptyline may result in a significantly
longer plasma half-life, higher AUC, and lower clearance of nortriptyline.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported
with SNRIs and SSRIs, including Pamelor, alone but particularly with concomitant use
of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair
metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g.,
tremor,
rigidity,
myoclonus,
hyperreflexia,
incoordination),
seizures,
and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be
monitored for the emergence of serotonin syndrome.
The concomitant use of Pamelor with MAOIs intended to treat psychiatric disorders is
contraindicated. Pamelor should also not be started in a patient who is being treated
with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene
blue that provided information on the route of administration involved intravenous
administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the
administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a patient
Page 5 of 15
10_2012.2
Reference ID: 3209061
taking Pamelor. Pamelor should be discontinued before initiating treatment with the
MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Pamelor with other serotonergic drugs, including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort
is clinically warranted, patients should be made aware of a potential increased risk for
serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Pamelor and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic
treatment should be initiated.
Use in Pregnancy
Safe use of Pamelor during pregnancy and lactation has not been established;
therefore, when the drug is administered to pregnant patients, nursing mothers, or
women of childbearing potential, the potential benefits must be weighed against the
possible hazards. Animal reproduction studies have yielded inconclusive results.
PRECAUTIONS
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with nortriptyline
hydrochloride and should counsel them in its appropriate use. A patient Medication
Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness,
and Suicidal Thoughts or Actions” is available for nortriptyline hydrochloride. The
prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its
contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete
text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if
these occur while taking nortriptyline hydrochloride.
Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient’s prescriber
or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
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The use of Pamelor in schizophrenic patients may result in an exacerbation of the
psychosis or may activate latent schizophrenic symptoms. If the drug is given to
overactive or agitated patients, increased anxiety and agitation may occur. In manic-
depressive patients, Pamelor may cause symptoms of the manic phase to emerge.
Troublesome patient hostility may be aroused by the use of Pamelor. Epileptiform
seizures may accompany its administration, as is true of other drugs of its class.
When it is essential, the drug may be administered with electroconvulsive therapy,
although the hazards may be increased. Discontinue the drug for several days, if
possible, prior to elective surgery.
The possibility of a suicidal attempt by a depressed patient remains after the initiation of
treatment; in this regard, it is important that the least possible quantity of drug be
dispensed at any given time.
Both elevation and lowering of blood sugar levels have been reported.
Drug Interactions
Administration of reserpine during therapy with a tricyclic antidepressant has been
shown to produce a “stimulating” effect in some depressed patients.
Close supervision and careful adjustment of the dosage are required when Pamelor is
used with other anticholinergic drugs and sympathomimetic drugs.
Concurrent administration of cimetidine and tricyclic antidepressants can produce
clinically significant increases in the plasma concentrations of the tricyclic
antidepressant. The patient should be informed that the response to alcohol may be
exaggerated.
A case of significant hypoglycemia has been reported in a type II diabetic patient
maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline
(125 mg/day).
Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the
Caucasian population (about 7% to 10% of Caucasians are so called “poor
metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of tricyclic
antidepressants (TCAs) when given usual doses. Depending on the fraction of drug
metabolized by P450 2D6, the increase in plasma concentration may be small, or quite
large (8 fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal
metabolizers resemble poor metabolizers. An individual who is stable on a given dose
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of TCA may become abruptly toxic when given one of these inhibiting drugs as
concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are
not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for
P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C
antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake
inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they
may vary in the extent of inhibition. The extent to which SSRI TCA interactions may
pose clinical problems will depend on the degree of inhibition and the pharmacokinetics
of the SSRI involved. Nevertheless, caution is indicated in the co-administration of
TCAs with any of the SSRIs and also in switching from one class to the other. Of
particular importance, sufficient time must elapse before initiating TCA treatment in a
patient being withdrawn from fluoxetine, given the long half-life of the parent and active
metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome
P450 2D6 may require lower doses than usually prescribed for either the tricyclic
antidepressant or the other drug. Furthermore, whenever one of these other drugs is
withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be
required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be
co-administered with another drug known to be an inhibitor of P450 2D6.
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Serotonergic Drugs
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see
BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone
considering the use of nortriptyline hydrochloride in a child or adolescent must balance
the potential risks with the clinical need.
Geriatric Use
Clinical studies of Pamelor did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other
reported clinical experience indicates that, as with other tricyclic antidepressants,
hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes)
are observed very rarely in geriatric patients and deaths associated with cholestatic liver
damage have been reported in isolated instances. Cardiovascular function, particularly
arrhythmias and fluctuations in blood pressure, should be monitored. There have also
been reports of confusional states following tricyclic antidepressant administration in the
elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10
hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic
antidepressants, dose selection for an elderly patient should usually be limited to the
smallest effective total daily dose (see DOSAGE AND ADMINISTRATION).
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ADVERSE REACTIONS
Note – Included in the following list are a few adverse reactions that have not been
reported with this specific drug. However, the pharmacologic similarities among the
tricyclic antidepressant drugs require that each of the reactions be considered when
nortriptyline is administered.
Cardiovascular – Hypotension, hypertension, tachycardia, palpitation, myocardial
infarction, arrhythmias, heart block, stroke.
Psychiatric – Confusional states (especially in the elderly) with hallucinations,
disorientation, delusions; anxiety, restlessness, agitation; insomnia, panic, nightmares;
hypomania; exacerbation of psychosis.
Neurologic – Numbness, tingling, paresthesias of extremities; incoordination, ataxia,
tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alteration in EEG
patterns; tinnitus.
Anticholinergic – Dry mouth and, rarely, associated sublingual adenitis; blurred vision,
disturbance of accommodation, mydriasis; constipation, paralytic ileus; urinary retention,
delayed micturition, dilation of the urinary tract.
Allergic – Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive
exposure to sunlight); edema (general or of face and tongue), drug fever, cross-
sensitivity with other tricyclic drugs.
Hematologic – Bone marrow depression, including agranulocytosis; eosinophilia;
purpura; thrombocytopenia.
Gastrointestinal – Nausea and vomiting, anorexia, epigastric distress, diarrhea,
peculiar taste, stomatitis, abdominal cramps, blacktongue.
Endocrine – Gynecomastia in the male, breast enlargement and galactorrhea in the
female; increased or decreased libido, impotence; testicular swelling; elevation or
depression of blood sugar levels; syndrome of inappropriate ADH (antidiuretic hormone)
secretion.
Other – Jaundice (simulating obstructive), altered liver function; weight gain or loss;
perspiration; flushing; urinary frequency, nocturia; drowsiness, dizziness, weakness,
fatigue; headache; parotid swelling; alopecia.
Withdrawal Symptoms – Though these are not indicative of addiction, abrupt
cessation of treatment after prolonged therapy may produce nausea, headache, and
malaise.
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion
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(including alcohol) is common in deliberate tricyclic antidepressant overdose. As the
management is complex and changing, it is recommended that the physician contact a
poison control center for current information on treatment. Signs and symptoms of
toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital
monitoring is required as soon as possible.
Manifestations
Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension,
shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression,
including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are
clinically significant indicators of tricyclic antidepressant toxicity.
Other signs of overdose may include: confusion, restlessness, disturbed concentration,
transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor,
drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the acute
symptoms listed under ADVERSE REACTIONS. There have been reports of patients
recovering from nortriptyline overdoses of up to 525 mg.
Management
General – Obtain an ECG and immediately initiate cardiac monitoring. Protect the
patient’s airway, establish an intravenous line and initiate gastric decontamination. A
minimum of six hours of observation with cardiac monitoring and observation for signs
of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction
blocks, and seizures is necessary. If signs of toxicity occur at any time during this
period, extended monitoring is required. There are case reports of patients succumbing
to fatal dysrhythmias late after overdose; these patients had clinical evidence of
significant poisoning prior to death and most received inadequate gastrointestinal
decontamination. Monitoring of plasma drug levels should not guide management of the
patient.
Gastrointestinal Decontamination – All patients suspected of tricyclic antidepressant
overdose should receive gastrointestinal decontamination. This should include large
volume gastric lavage followed by activated charcoal. If consciousness is impaired, the
airway should be secured prior to lavage. EMESIS IS CONTRAINDICATED.
Cardiovascular – A maximal limb-lead QRS duration of ≥0.10 seconds may be the best
indication of the severity of the overdose. Intravenous sodium bicarbonate should be
used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is
inadequate, hyperventilation may also be used. Concomitant use of hyperventilation
and sodium bicarbonate should be done with extreme caution, with frequent pH
monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias
unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine,
bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated
(e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion
may be beneficial in acute refractory cardiovascular instability in patients with acute
toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced
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diuresis generally have been reported as ineffective in tricyclic antidepressant
poisoning.
CNS – In patients with CNS depression, early intubation is advised because of the
potential for abrupt deterioration. Seizures should be controlled with benzodiazepines,
or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).
Physostigmine is not recommended except to treat life-threatening symptoms that have
been unresponsive to other therapies, and then only in consultation with a poison
control center.
Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt
suicide by other means during the recovery phase. Psychiatric referral may be
appropriate.
Pediatric Management – The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact the local
poison control center for specific pediatric treatment.
DOSAGE AND ADMINISTRATION
Pamelor is not recommended for children.
Pamelor is administered orally in the form of capsules or liquid. Lower than usual
dosages are recommended for elderly patients and adolescents. Lower dosages are
also recommended for outpatients than for hospitalized patients who will be under close
supervision. The physician should initiate dosage at a low level and increase it
gradually, noting carefully the clinical response and any evidence of intolerance.
Following remission, maintenance medication may be required for a longer period of
time at the lowest dose that will maintain remission.
If a patient develops minor side effects, the dosage should be reduced. The drug should
be discontinued promptly if adverse effects of a serious nature or allergic manifestations
occur.
Usual Adult Dose – 25 mg three or four times daily; dosage should begin at a low level
and be increased as required. As an alternate regimen, the total daily dosage may be
given once a day. When doses above 100 mg daily are administered, plasma levels of
nortriptyline should be monitored and maintained in the optimum range of 50 to
150 ng/mL. Doses above 150 mg/day are not recommended.
Elderly and Adolescent Patients – 30 to 50 mg/day, in divided doses, or the total daily
dosage may be given once a day.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended
to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat
psychiatric disorders and initiation of therapy with Pamelor. Conversely, at least 14 days
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should be allowed after stopping Pamelor before starting an MAOI intended to treat
psychiatric disorders (see CONTRAINDICATIONS).
Use of Pamelor With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start Pamelor in a patient who is being treated with linezolid or intravenous
methylene blue because there is increased risk of serotonin syndrome. In a patient who
requires more urgent treatment of a psychiatric condition, other interventions, including
hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving Pamelor therapy may require urgent
treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential
benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the
risks of serotonin syndrome in a particular patient, Pamelor should be stopped promptly,
and linezolid or intravenous methylene blue can be administered. The patient should be
monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the
last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy
with Pamelor may be resumed 24 hours after the last dose of linezolid or intravenous
methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral
tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with
Pamelor is unclear. The clinician should, nevertheless, be aware of the possibility of
emergent symptoms of serotonin syndrome with such use (see WARNINGS).
HOW SUPPLIED
Pamelor™ (nortriptyline HCl) Capsules USP
Pamelor™ (nortriptyline HCl) Capsules USP, equivalent to 10 mg, 25 mg, 50 mg, and
75 mg base, are available as follows:
10 mg: Light orange opaque cap printed “
PAMELOR 10 mg” in black and white
opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9910-03
25 mg: Light orange opaque cap printed “
PAMELOR 25 mg” in black and white
opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9911-03
50 mg: White opaque cap printed “
PAMELOR 50 mg” in black and white opaque
body printed “M” in black.
Bottles of 30 ............ NDC 0406-9912-03
75 mg: Light orange opaque cap printed “
PAMELOR 75 mg” in black and light
orange opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9913-03
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Store and Dispense
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in tight container (USP) with a child-resistant closure.
Pamelor™ (nortriptyline HCl) Oral Solution USP
Pamelor™ (nortriptyline HCl) oral solution USP, equivalent to 10 mg base per 5 mL, is
supplied in 16-fluid-ounce bottles (NDC 0406-9918-16). Alcohol content 4%.
Store and Dispense
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in tight, light-resistant container.
Pamelor and M are trademarks of Mallinckrodt LLC.
Capsules manufactured by:
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
Oral Solution manufactured by:
Novartis Consumer Health, Inc.
Lincoln, Nebraska 68517
Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Medication Guide – Pamelor™ (nortriptyline HCl) Capsules USP
and Oral Solution USP
Antidepressant Medicines, Depression and other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s
antidepressant medicine. This Medication Guide is only about the risk of suicidal
thoughts and actions with antidepressant medicines. Talk to your, or your family
member’s, healthcare provider about:
all risks and benefits of treatment with antidepressant medicines
all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant
medicines, depression and other serious mental illnesses, and suicidal thoughts
or actions?
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1. Antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes
of suicidal thoughts and actions. Some people may have a particularly high
risk of having suicidal thoughts or actions. These include people who have (or
have a family history of) bipolar illness (also called manic-depressive illness) or
suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself
or a family member?
Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call a healthcare provider right away if you or your family member has any of
the following symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling very agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
Who should not take Pamelor?
Do not take Pamelor if you:
take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
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o Do not take an MAOI within 2 weeks of stopping Pamelor unless directed to
do so by your physician.
o Do not start Pamelor if you stopped taking an MAOI in the last 2 weeks
unless directed to do so by your physician.
What else do I need to know about antidepressant medicines?
Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
Antidepressants are medicines used to treat depression and other illnesses. It
is important to discuss all the risks of treating depression and also the risks of not
treating it. Patients and their families or other caregivers should discuss all treatment
choices with the healthcare provider, not just the use of antidepressants.
Antidepressant medicines have other side effects. Talk to the healthcare provider
about the side effects of the medicine prescribed for you or your family member.
Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show
the healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
Not all antidepressant medicines prescribed for children are FDA approved for
use in children. Talk to your child’s healthcare provider for more information.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Pamelor is a trademark of Mallinckrodt LLC.
Capsules manufactured by:
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
Oral Solution manufactured by:
Novartis Consumer Health, Inc.
Lincoln, Nebraska 68517
Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Rev 10/2012
company logo
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2025-02-12T13:44:26.920542
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018012s029,018013s061lbl.pdf', 'application_number': 18012, 'submission_type': 'SUPPL ', 'submission_number': 29}
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Attachment 1
Page 1
Class Suicidality Labeling Language for Antidepressants
[This section should be located at the beginning of the package insert with bolded font and
enclosed in a black box]
[Insert established name]
Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term
studies in children and adolescents with Major Depressive Disorder (MDD) and other
psychiatric disorders. Anyone considering the use of [Insert established name] or any other
antidepressant in a child or adolescent must balance this risk with the clinical need. Patients
who are started on therapy should be observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. [Insert established name] is not approved
for use in pediatric patients. (See Warnings and Precautions: Pediatric Use)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs
(SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive
compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over
4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or
behavior (suicidality) during the first few months of treatment in those receiving
antidepressants. The average risk of such events in patients receiving antidepressants was 4%,
twice the placebo risk of 2%. No suicides occurred in these trials.
[This section should be located under WARNINGS. Please note that the title of this
section should be bolded, and it should be the first paragraph in this section.]
WARNINGS-Clinical Worsening and Suicide Risk
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. There has been a long-standing concern that antidepressants
may have a role in inducing worsening of depression and the emergence of suicidality in certain
patients. A causal role for antidepressants in inducing suicidality has been established in pediatric
patients.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in
children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving
over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or
thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The
average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 1
Page 2
There was considerable variation in risk among drugs, but a tendency toward an increase for almost
all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there
were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive
disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is
unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond
several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes, either increases or
decreases. Such observation would generally include at least weekly face-to-face contact with
patients or their family members or caregivers during the first 4 weeks of treatment, then every
other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12
weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being
treated with antidepressants should be observed similarly for clinical worsening and suicidality,
especially during the initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adult and pediatric patients being treated with antidepressants for major depressive disorder
as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between
the emergence of such symptoms and either the worsening of depression and/or the emergence of
suicidal impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of pediatric patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted
about the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality, and
to report such symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for [Insert established name] should be
written for the smallest quantity of tablets consistent with good patient management, in order to reduce
the risk of overdose. Families and caregivers of adults being treated for depression should be similarly
advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled trials) that treating
such an episode with an antidepressant alone may increase the likelihood of precipitation of a
mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 1
Page 3
above represent such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a
family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established
name] is not approved for use in treating bipolar depression.
[This section should be located under PRECAUTIONS, Information for Patients.]
Prescribers or other health professionals should inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with [Insert established name] and should
counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in
Children and Adolescents is available for [Insert established name]. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication Guide
and should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur
while taking [Insert established name].
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual
changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant
treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised
to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
symptoms should be reported to the patient's prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be
associated with an increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
[This section should be located under PRECAUTIONS, Pediatric Use.]
Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX
WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of
[Insert established name] in a child or adolescent must balance the potential risks with the clinical
need.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 1
Medication Guide
About Using Antidepressants in Children and Teenagers
What is the most important information I should know if my child is being prescribed an
antidepressant?
Parents or guardians need to think about 4 important things when their child is prescribed an
antidepressant:
1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants
1. There is a Risk of Suicidal Thoughts or Actions
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal
thoughts and actions can also be caused by depression, a serious medical condition that is commonly
treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called
suicidality or being suicidal.
A large study combined the results of 24 different studies of children and teenagers with depression or
other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to
4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar
pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became
suicidal.
For some children and teenagers, the risks of suicidal actions may be especially high. These
include patients with
• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide
If any of these are present, make sure you tell your healthcare provider before your child takes an
antidepressant.
2. How to Try to Prevent Suicidal Thoughts and Actions
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or
his moods or actions, especially if the changes occur suddenly. Other important people in your child's
life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other
important people). The changes to look out for are listed in Section 3, on what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 2
After starting an antidepressant, your child should generally see his or her healthcare provider:
• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider's advice about how often to come back
• More often if problems or questions arise (see other side)
You should call your child's healthcare provider between visits if needed.
3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant
Contact your child's healthcare provider right away if your child exhibits any of the following signs for
the first time, or if they seem worse, or worry you, your child, or your child's teacher:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood
Never let your child stop taking an antidepressant without first talking to his or her healthcare
provider. Stopping an antidepressant suddenly can cause other symptoms.
4. There are Benefits and Risks When Using Antidepressants
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can
lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal
thinking or actions. It is important to discuss all the risks of treating depression and also the risks of
not treating it. You and your child should discuss all treatment choices with your healthcare provider,
not just the use of antidepressants.
Other side effects can occur with antidepressants (see section below).
Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric
depression.
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
(ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) .
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 3
Your healthcare provider may suggest other antidepressants based on the past experience of your child
or other family members.
Is this all I need to know if my child is being prescribed an antidepressant?
No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants.
Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is
prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare
provider or pharmacist where to find more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:27.237772
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/18012s026,18013s056lbl.pdf', 'application_number': 18013, 'submission_type': 'SUPPL ', 'submission_number': 56}
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11,112
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Pamelor™
(nortriptyline HCl) oral solution USP
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term
studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of nortriptyline hydrochloride or any other
antidepressant in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24;
there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately
and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Nortriptyline hydrochloride
is not approved for use in pediatric patients (see WARNINGS, Clinical Worsening
and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS,
Pediatric Use).
DESCRIPTION
Pamelor™
(nortriptyline
HCl)
is
1-propanamine,
3-(10,11-dihydro-5H
dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-, hydrochloride.
The structural formula is as follows: structural formula
C19H21N•HCl
MW = 299.84
Solution
Active Ingredient: nortriptyline hydrochloride USP.
Inactive Ingredients: alcohol, benzoic acid, flavoring, purified water, and sorbitol.
CLINICAL PHARMACOLOGY
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The mechanism of mood elevation by tricyclic antidepressants is at present unknown.
Pamelor is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse
agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor
effect of norepinephrine but blocks the pressor response of phenethylamine. Studies
suggest that Pamelor interferes with the transport, release, and storage of
catecholamines. Operant conditioning techniques in rats and pigeons suggest that
Pamelor has a combination of stimulant and depressant properties.
INDICATIONS AND USAGE
Pamelor™ (nortriptyline HCl) is indicated for the relief of symptoms of depression.
Endogenous depressions are more likely to be alleviated than are other depressive
states.
CONTRAINDICATIONS
Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with Pamelor or within 14 days
of stopping treatment with Pamelor is contraindicated because of an increased risk of
serotonin syndrome. The use of Pamelor within 14 days of stopping an MAOI intended
to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE
AND ADMINISTRATION).
Starting Pamelor in a patient who is being treated with MAOIs such as linezolid or
intravenous methylene blue is also contraindicated because of an increased risk of
serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Hypersensitivity to Tricyclic Antidepressants
Cross-sensitivity between Pamelor and other dibenzazepines is a possibility.
Myocardial Infarction
Pamelor is contraindicated during the acute recovery period after myocardial infarction.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation and
behavior (suicidality) or unusual changes in behavior, whether or not they are taking
antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-
standing concern, however, that antidepressants may have a role in inducing worsening
of depression and the emergence of suicidality in certain patients during the early
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phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
(ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction
with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders
included a total of 295 short-term trials (median duration of 2 months) of 11
antidepressant drugs in over 77,000 patients. There was considerable variation in risk of
suicidality among drugs, but a tendency toward an increase in the younger patients for
almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per
1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Increases Compared to Placebo
<18
18-24
14 additional cases
5 additional cases
Decreases Compared to Placebo
25-64
≥65
1 fewer case
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond
several months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants can delay
the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of a
course of drug therapy, or at times of dose changes, either increases or
decreases.
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The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and
mania, have been reported in adult and pediatric patients being treated with
antidepressants for major depressive disorder as well as for other indications, both
psychiatric and nonpsychiatric. Although a causal link between the emergence of such
symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who
are experiencing emergent suicidality or symptoms that might be precursors to
worsening depression or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of
agitation, irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report such
symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for nortriptyline
hydrochloride should be written for the smallest volume of oral solutionconsistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder – A major depressive episode may be the
initial presentation of bipolar disorder. It is generally believed (though not established in
controlled trials) that treating such an episode with an antidepressant alone may
increase the likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an antidepressant,
patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that nortriptyline hydrochloride is not approved for use in treating bipolar
depression.
Patients with cardiovascular disease should be given Pamelor only under close
supervision because of the tendency of the drug to produce sinus tachycardia and to
prolong the conduction time. Myocardial infarction, arrhythmia, and strokes have
occurred. The antihypertensive action of guanethidine and similar agents may be
blocked. Because of its anticholinergic activity, Pamelor should be used with great
caution in patients who have a history of urinary retention. Patients with a history of
seizures should be followed closely when Pamelor is administered, inasmuch as this
drug is known to lower the convulsive threshold. Great care is required if Pamelor is
given to hyperthyroid patients or to those receiving thyroid medication, since cardiac
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arrhythmias may develop.
Pamelor may impair the mental and/or physical abilities required for the performance of
hazardous tasks, such as operating machinery or driving a car; therefore, the patient
should be warned accordingly.
Excessive consumption of alcohol in combination with nortriptyline therapy may have a
potentiating effect, which may lead to the danger of increased suicidal attempts or
overdosage, especially in patients with histories of emotional disturbances or suicidal
ideation.
The concomitant administration of quinidine and nortriptyline may result in a significantly
longer plasma half-life, higher AUC, and lower clearance of nortriptyline.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported
with SNRIs and SSRIs, including Pamelor, alone but particularly with concomitant use
of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair
metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g.,
tremor,
rigidity,
myoclonus,
hyperreflexia,
incoordination),
seizures,
and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be
monitored for the emergence of serotonin syndrome.
The concomitant use of Pamelor with MAOIs intended to treat psychiatric disorders is
contraindicated. Pamelor should also not be started in a patient who is being treated
with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene
blue that provided information on the route of administration involved intravenous
administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the
administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a patient
taking Pamelor. Pamelor should be discontinued before initiating treatment with the
MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Pamelor with other serotonergic drugs, including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort
is clinically warranted, patients should be made aware of a potential increased risk for
serotonin syndrome, particularly during treatment initiation and dose increases.
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Treatment with Pamelor and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic
treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including
Pamelor may trigger an angle-closure attack in a patient with anatomically narrow
angles who does not have a patent iridectomy.
Use in Pregnancy
Safe use of Pamelor during pregnancy and lactation has not been established;
therefore, when the drug is administered to pregnant patients, nursing mothers, or
women of childbearing potential, the potential benefits must be weighed against the
possible hazards. Animal reproduction studies have yielded inconclusive results.
PRECAUTIONS
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with nortriptyline
hydrochloride and should counsel them in its appropriate use. A patient Medication
Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness,
and Suicidal Thoughts or Actions” is available for nortriptyline hydrochloride. The
prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its
contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete
text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if
these occur while taking nortriptyline hydrochloride.
Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient’s prescriber
or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
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The use of Pamelor in schizophrenic patients may result in an exacerbation of the
psychosis or may activate latent schizophrenic symptoms. If the drug is given to
overactive or agitated patients, increased anxiety and agitation may occur. In manic-
depressive patients, Pamelor may cause symptoms of the manic phase to emerge.
Troublesome patient hostility may be aroused by the use of Pamelor. Epileptiform
seizures may accompany its administration, as is true of other drugs of its class.
When it is essential, the drug may be administered with electroconvulsive therapy,
although the hazards may be increased. Discontinue the drug for several days, if
possible, prior to elective surgery.
The possibility of a suicidal attempt by a depressed patient remains after the initiation of
treatment; in this regard, it is important that the least possible quantity of drug be
dispensed at any given time.
Both elevation and lowering of blood sugar levels have been reported.
Patients should be advised that taking Pamelor can cause mild pupillary dilation, which
in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre
existing glaucoma is almost always open-angle glaucoma because angle-closure
glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle
glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be
examined to determine whether they are susceptible to angle closure, and have a
prophylactic procedure (e.g., iridectomy), if they are susceptible.
Drug Interactions
Administration of reserpine during therapy with a tricyclic antidepressant has been
shown to produce a “stimulating” effect in some depressed patients.
Close supervision and careful adjustment of the dosage are required when Pamelor is
used with other anticholinergic drugs and sympathomimetic drugs.
Concurrent administration of cimetidine and tricyclic antidepressants can produce
clinically significant increases in the plasma concentrations of the tricyclic
antidepressant. The patient should be informed that the response to alcohol may be
exaggerated.
A case of significant hypoglycemia has been reported in a type II diabetic patient
maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline
(125 mg/day).
Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the
Caucasian population (about 7% to 10% of Caucasians are so called “poor
metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme
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activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of tricyclic
antidepressants (TCAs) when given usual doses. Depending on the fraction of drug
metabolized by P450 2D6, the increase in plasma concentration may be small, or quite
large (8 fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal
metabolizers resemble poor metabolizers. An individual who is stable on a given dose
of TCA may become abruptly toxic when given one of these inhibiting drugs as
concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are
not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for
P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C
antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake
inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they
may vary in the extent of inhibition. The extent to which SSRI TCA interactions may
pose clinical problems will depend on the degree of inhibition and the pharmacokinetics
of the SSRI involved. Nevertheless, caution is indicated in the co-administration of
TCAs with any of the SSRIs and also in switching from one class to the other. Of
particular importance, sufficient time must elapse before initiating TCA treatment in a
patient being withdrawn from fluoxetine, given the long half-life of the parent and active
metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome
P450 2D6 may require lower doses than usually prescribed for either the tricyclic
antidepressant or the other drug. Furthermore, whenever one of these other drugs is
withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be
required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be
co-administered with another drug known to be an inhibitor of P450 2D6.
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Serotonergic Drugs
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see
BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone
considering the use of nortriptyline hydrochloride in a child or adolescent must balance
the potential risks with the clinical need.
Geriatric Use
Clinical studies of Pamelor did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other
reported clinical experience indicates that, as with other tricyclic antidepressants,
hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes)
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are observed very rarely in geriatric patients and deaths associated with cholestatic liver
damage have been reported in isolated instances. Cardiovascular function, particularly
arrhythmias and fluctuations in blood pressure, should be monitored. There have also
been reports of confusional states following tricyclic antidepressant administration in the
elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10
hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic
antidepressants, dose selection for an elderly patient should usually be limited to the
smallest effective total daily dose (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Note – Included in the following list are a few adverse reactions that have not been
reported with this specific drug. However, the pharmacologic similarities among the
tricyclic antidepressant drugs require that each of the reactions be considered when
nortriptyline is administered.
Cardiovascular – Hypotension, hypertension, tachycardia, palpitation, myocardial
infarction, arrhythmias, heart block, stroke.
Psychiatric – Confusional states (especially in the elderly) with hallucinations,
disorientation, delusions; anxiety, restlessness, agitation; insomnia, panic, nightmares;
hypomania; exacerbation of psychosis.
Neurologic – Numbness, tingling, paresthesias of extremities; incoordination, ataxia,
tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alteration in EEG
patterns; tinnitus.
Anticholinergic – Dry mouth and, rarely, associated sublingual adenitis; blurred vision,
disturbance of accommodation, mydriasis; constipation, paralytic ileus; urinary retention,
delayed micturition, dilation of the urinary tract.
Allergic – Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive
exposure to sunlight); edema (general or of face and tongue), drug fever, cross-
sensitivity with other tricyclic drugs.
Hematologic – Bone marrow depression, including agranulocytosis; eosinophilia;
purpura; thrombocytopenia.
Gastrointestinal – Nausea and vomiting, anorexia, epigastric distress, diarrhea,
peculiar taste, stomatitis, abdominal cramps, blacktongue.
Endocrine – Gynecomastia in the male, breast enlargement and galactorrhea in the
female; increased or decreased libido, impotence; testicular swelling; elevation or
depression of blood sugar levels; syndrome of inappropriate ADH (antidiuretic hormone)
secretion.
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Other – Jaundice (simulating obstructive), altered liver function; weight gain or loss;
perspiration; flushing; urinary frequency, nocturia; drowsiness, dizziness, weakness,
fatigue; headache; parotid swelling; alopecia.
Withdrawal Symptoms – Though these are not indicative of addiction, abrupt
cessation of treatment after prolonged therapy may produce nausea, headache, and
malaise.
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion
(including alcohol) is common in deliberate tricyclic antidepressant overdose. As the
management is complex and changing, it is recommended that the physician contact a
poison control center for current information on treatment. Signs and symptoms of
toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital
monitoring is required as soon as possible.
Manifestations
Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension,
shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression,
including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are
clinically significant indicators of tricyclic antidepressant toxicity.
Other signs of overdose may include: confusion, restlessness, disturbed concentration,
transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor,
drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the acute
symptoms listed under ADVERSE REACTIONS. There have been reports of patients
recovering from nortriptyline overdoses of up to 525 mg.
Management
General – Obtain an ECG and immediately initiate cardiac monitoring. Protect the
patient’s airway, establish an intravenous line and initiate gastric decontamination. A
minimum of six hours of observation with cardiac monitoring and observation for signs
of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction
blocks, and seizures is necessary. If signs of toxicity occur at any time during this
period, extended monitoring is required. There are case reports of patients succumbing
to fatal dysrhythmias late after overdose; these patients had clinical evidence of
significant poisoning prior to death and most received inadequate gastrointestinal
decontamination. Monitoring of plasma drug levels should not guide management of the
patient.
Gastrointestinal Decontamination – All patients suspected of tricyclic antidepressant
overdose should receive gastrointestinal decontamination. This should include large
volume gastric lavage followed by activated charcoal. If consciousness is impaired, the
airway should be secured prior to lavage. EMESIS IS CONTRAINDICATED.
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Cardiovascular – A maximal limb-lead QRS duration of ≥0.10 seconds may be the best
indication of the severity of the overdose. Intravenous sodium bicarbonate should be
used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is
inadequate, hyperventilation may also be used. Concomitant use of hyperventilation
and sodium bicarbonate should be done with extreme caution, with frequent pH
monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias
unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine,
bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated
(e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion
may be beneficial in acute refractory cardiovascular instability in patients with acute
toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced
diuresis generally have been reported as ineffective in tricyclic antidepressant
poisoning.
CNS – In patients with CNS depression, early intubation is advised because of the
potential for abrupt deterioration. Seizures should be controlled with benzodiazepines,
or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).
Physostigmine is not recommended except to treat life-threatening symptoms that have
been unresponsive to other therapies, and then only in consultation with a poison
control center.
Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt
suicide by other means during the recovery phase. Psychiatric referral may be
appropriate.
Pediatric Management – The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact the local
poison control center for specific pediatric treatment.
DOSAGE AND ADMINISTRATION
Pamelor is not recommended for children.
Pamelor is administered orally in the form oforal solution.. Lower than usual dosages
are recommended for elderly patients and adolescents. Lower dosages are also
recommended for outpatients than for hospitalized patients who will be under close
supervision. The physician should initiate dosage at a low level and increase it
gradually, noting carefully the clinical response and any evidence of intolerance.
Following remission, maintenance medication may be required for a longer period of
time at the lowest dose that will maintain remission.
If a patient develops minor side effects, the dosage should be reduced. The drug should
be discontinued promptly if adverse effects of a serious nature or allergic manifestations
occur.
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Usual Adult Dose – 25 mg three or four times daily; dosage should begin at a low level
and be increased as required. As an alternate regimen, the total daily dosage may be
given once a day. When doses above 100 mg daily are administered, plasma levels of
nortriptyline should be monitored and maintained in the optimum range of 50 to
150 ng/mL. Doses above 150 mg/day are not recommended.
Elderly and Adolescent Patients – 30 to 50 mg/day, in divided doses, or the total daily
dosage may be given once a day.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended
to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat
psychiatric disorders and initiation of therapy with Pamelor. Conversely, at least 14 days
should be allowed after stopping Pamelor before starting an MAOI intended to treat
psychiatric disorders (see CONTRAINDICATIONS).
Use of Pamelor With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start Pamelor in a patient who is being treated with linezolid or intravenous
methylene blue because there is increased risk of serotonin syndrome. In a patient who
requires more urgent treatment of a psychiatric condition, other interventions, including
hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving Pamelor therapy may require urgent
treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential
benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the
risks of serotonin syndrome in a particular patient, Pamelor should be stopped promptly,
and linezolid or intravenous methylene blue can be administered. The patient should be
monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the
last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy
with Pamelor may be resumed 24 hours after the last dose of linezolid or intravenous
methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral
tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with
Pamelor is unclear. The clinician should, nevertheless, be aware of the possibility of
emergent symptoms of serotonin syndrome with such use (see WARNINGS).
HOW SUPPLIED
Pamelor™ (nortriptyline HCl) Oral Solution USP
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Pamelor™ (nortriptyline HCl) oral solution USP, equivalent to 10 mg base per 5 mL, is
supplied in 16-fluid-ounce bottles (NDC 0406-9918-16). Alcohol content 4%.
Store and Dispense
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in tight, light-resistant container.
Pamelor and M are trademarks of Mallinckrodt LLC.
Manufactured by:
Novartis Consumer Health, Inc.
Lincoln, Nebraska 68517
Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Medication Guide – Pamelor™ (nortriptyline HCl) Oral Solution USP
Antidepressant Medicines, Depression and other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s
antidepressant medicine. This Medication Guide is only about the risk of suicidal
thoughts and actions with antidepressant medicines. Talk to your, or your family
member’s, healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant
medicines, depression and other serious mental illnesses, and suicidal thoughts
or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes
of suicidal thoughts and actions. Some people may have a particularly high
risk of having suicidal thoughts or actions. These include people who have (or
have a family history of) bipolar illness (also called manic-depressive illness) or
suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself
or a family member?
• Pay close attention to any changes, especially sudden changes, in mood,
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behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call a healthcare provider right away if you or your family member has any of
the following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
Visual problems
• eye pain
• changes in vision
• swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an eye
examination to see if you are at risk and receive preventative treatment if you are.
Who should not take Pamelor?
Do not take Pamelor if you:
• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
o Do not take an MAOI within 2 weeks of stopping Pamelor unless directed to
do so by your physician.
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o Do not start Pamelor if you stopped taking an MAOI in the last 2 weeks
unless directed to do so by your physician.
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It
is important to discuss all the risks of treating depression and also the risks of not
treating it. Patients and their families or other caregivers should discuss all treatment
choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider
about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show
the healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for
use in children. Talk to your child’s healthcare provider for more information.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Pamelor is a trademark of Mallinckrodt LLC.
Manufactured by:
Novartis Consumer Health, Inc.
Lincoln, Nebraska 68517
Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Rev 05/2014 company logo
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|
custom-source
|
2025-02-12T13:44:27.447949
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018012s030lbl.pdf', 'application_number': 18012, 'submission_type': 'SUPPL ', 'submission_number': 30}
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Pamelor™
(nortriptyline HCl) capsules USP
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term
studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of nortriptyline hydrochloride or any other
antidepressant in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24;
there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately
and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Nortriptyline hydrochloride
is not approved for use in pediatric patients (see WARNINGS, Clinical Worsening
and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS,
Pediatric Use).
DESCRIPTION
Pamelor™
(nortriptyline
HCl)
is
1-propanamine,
3-(10,11-dihydro-5H
dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-, hydrochloride.
The structural formula is as follows: structural formula
C19H21N•HCl
MW = 299.84
10 mg, 25 mg, 50 mg, and 75 mg Capsules
Active Ingredient: nortriptyline hydrochloride USP.
10 mg, 25 mg, and 75 mg Capsules
Inactive Ingredients: D&C Yellow #10, FD&C Yellow #6, gelatin, silicone fluid, starch,
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and titanium dioxide.
50 mg Capsules
Inactive Ingredients: gelatin, silicone fluid, starch, and titanium dioxide.
CLINICAL PHARMACOLOGY
The mechanism of mood elevation by tricyclic antidepressants is at present unknown.
Pamelor is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse
agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor
effect of norepinephrine but blocks the pressor response of phenethylamine. Studies
suggest that Pamelor interferes with the transport, release, and storage of
catecholamines. Operant conditioning techniques in rats and pigeons suggest that
Pamelor has a combination of stimulant and depressant properties.
INDICATIONS AND USAGE
Pamelor™ (nortriptyline HCl) is indicated for the relief of symptoms of depression.
Endogenous depressions are more likely to be alleviated than are other depressive
states.
CONTRAINDICATIONS
Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with Pamelor or within 14 days
of stopping treatment with Pamelor is contraindicated because of an increased risk of
serotonin syndrome. The use of Pamelor within 14 days of stopping an MAOI intended
to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE
AND ADMINISTRATION).
Starting Pamelor in a patient who is being treated with MAOIs such as linezolid or
intravenous methylene blue is also contraindicated because of an increased risk of
serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Hypersensitivity to Tricyclic Antidepressants
Cross-sensitivity between Pamelor and other dibenzazepines is a possibility.
Myocardial Infarction
Pamelor is contraindicated during the acute recovery period after myocardial infarction.
WARNINGS
Clinical Worsening and Suicide Risk
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Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation and
behavior (suicidality) or unusual changes in behavior, whether or not they are taking
antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-
standing concern, however, that antidepressants may have a role in inducing worsening
of depression and the emergence of suicidality in certain patients during the early
phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
(ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction
with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders
included a total of 295 short-term trials (median duration of 2 months) of 11
antidepressant drugs in over 77,000 patients. There was considerable variation in risk of
suicidality among drugs, but a tendency toward an increase in the younger patients for
almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per
1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Increases Compared to Placebo
<18
18-24
14 additional cases
5 additional cases
Decreases Compared to Placebo
25-64
≥65
1 fewer case
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond
several months. However, there is substantial evidence from placebo-controlled
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maintenance trials in adults with depression that the use of antidepressants can delay
the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of a
course of drug therapy, or at times of dose changes, either increases or
decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and
mania, have been reported in adult and pediatric patients being treated with
antidepressants for major depressive disorder as well as for other indications, both
psychiatric and nonpsychiatric. Although a causal link between the emergence of such
symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who
are experiencing emergent suicidality or symptoms that might be precursors to
worsening depression or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of
agitation, irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report such
symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for nortriptyline
hydrochloride should be written for the smallest quantity of capsules consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder – A major depressive episode may be the
initial presentation of bipolar disorder. It is generally believed (though not established in
controlled trials) that treating such an episode with an antidepressant alone may
increase the likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an antidepressant,
patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that nortriptyline hydrochloride is not approved for use in treating bipolar
depression.
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Patients with cardiovascular disease should be given Pamelor only under close
supervision because of the tendency of the drug to produce sinus tachycardia and to
prolong the conduction time. Myocardial infarction, arrhythmia, and strokes have
occurred. The antihypertensive action of guanethidine and similar agents may be
blocked. Because of its anticholinergic activity, Pamelor should be used with great
caution in patients who have a history of urinary retention. Patients with a history of
seizures should be followed closely when Pamelor is administered, inasmuch as this
drug is known to lower the convulsive threshold. Great care is required if Pamelor is
given to hyperthyroid patients or to those receiving thyroid medication, since cardiac
arrhythmias may develop.
Pamelor may impair the mental and/or physical abilities required for the performance of
hazardous tasks, such as operating machinery or driving a car; therefore, the patient
should be warned accordingly.
Excessive consumption of alcohol in combination with nortriptyline therapy may have a
potentiating effect, which may lead to the danger of increased suicidal attempts or
overdosage, especially in patients with histories of emotional disturbances or suicidal
ideation.
The concomitant administration of quinidine and nortriptyline may result in a significantly
longer plasma half-life, higher AUC, and lower clearance of nortriptyline.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported
with SNRIs and SSRIs, including Pamelor, alone but particularly with concomitant use
of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair
metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g.,
tremor,
rigidity,
myoclonus,
hyperreflexia,
incoordination),
seizures,
and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be
monitored for the emergence of serotonin syndrome.
The concomitant use of Pamelor with MAOIs intended to treat psychiatric disorders is
contraindicated. Pamelor should also not be started in a patient who is being treated
with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene
blue that provided information on the route of administration involved intravenous
administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the
administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a patient
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taking Pamelor. Pamelor should be discontinued before initiating treatment with the
MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Pamelor with other serotonergic drugs, including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort
is clinically warranted, patients should be made aware of a potential increased risk for
serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Pamelor and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic
treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including
Pamelor may trigger an angle-closure attack in a patient with anatomically narrow
angles who does not have a patent iridectomy.
Use in Pregnancy
Safe use of Pamelor during pregnancy and lactation has not been established;
therefore, when the drug is administered to pregnant patients, nursing mothers, or
women of childbearing potential, the potential benefits must be weighed against the
possible hazards. Animal reproduction studies have yielded inconclusive results.
PRECAUTIONS
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with nortriptyline
hydrochloride and should counsel them in its appropriate use. A patient Medication
Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness,
and Suicidal Thoughts or Actions” is available for nortriptyline hydrochloride. The
prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its
contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete
text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if
these occur while taking nortriptyline hydrochloride.
Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and
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when the dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient’s prescriber
or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
The use of Pamelor in schizophrenic patients may result in an exacerbation of the
psychosis or may activate latent schizophrenic symptoms. If the drug is given to
overactive or agitated patients, increased anxiety and agitation may occur. In manic-
depressive patients, Pamelor may cause symptoms of the manic phase to emerge.
Troublesome patient hostility may be aroused by the use of Pamelor. Epileptiform
seizures may accompany its administration, as is true of other drugs of its class.
When it is essential, the drug may be administered with electroconvulsive therapy,
although the hazards may be increased. Discontinue the drug for several days, if
possible, prior to elective surgery.
The possibility of a suicidal attempt by a depressed patient remains after the initiation of
treatment; in this regard, it is important that the least possible quantity of drug be
dispensed at any given time.
Both elevation and lowering of blood sugar levels have been reported.
Patients should be advised that taking Pamelor can cause mild pupillary dilation, which
in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre
existing glaucoma is almost always open-angle glaucoma because angle-closure
glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle
glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be
examined to determine whether they are susceptible to angle closure, and have a
prophylactic procedure (e.g., iridectomy), if they are susceptible.
Drug Interactions
Administration of reserpine during therapy with a tricyclic antidepressant has been
shown to produce a “stimulating” effect in some depressed patients.
Close supervision and careful adjustment of the dosage are required when Pamelor is
used with other anticholinergic drugs and sympathomimetic drugs.
Concurrent administration of cimetidine and tricyclic antidepressants can produce
clinically significant increases in the plasma concentrations of the tricyclic
antidepressant. The patient should be informed that the response to alcohol may be
exaggerated.
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A case of significant hypoglycemia has been reported in a type II diabetic patient
maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline
(125 mg/day).
Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the
Caucasian population (about 7% to 10% of Caucasians are so called “poor
metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of tricyclic
antidepressants (TCAs) when given usual doses. Depending on the fraction of drug
metabolized by P450 2D6, the increase in plasma concentration may be small, or quite
large (8 fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal
metabolizers resemble poor metabolizers. An individual who is stable on a given dose
of TCA may become abruptly toxic when given one of these inhibiting drugs as
concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are
not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for
P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C
antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake
inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they
may vary in the extent of inhibition. The extent to which SSRI TCA interactions may
pose clinical problems will depend on the degree of inhibition and the pharmacokinetics
of the SSRI involved. Nevertheless, caution is indicated in the co-administration of
TCAs with any of the SSRIs and also in switching from one class to the other. Of
particular importance, sufficient time must elapse before initiating TCA treatment in a
patient being withdrawn from fluoxetine, given the long half-life of the parent and active
metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome
P450 2D6 may require lower doses than usually prescribed for either the tricyclic
antidepressant or the other drug. Furthermore, whenever one of these other drugs is
withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be
required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be
co-administered with another drug known to be an inhibitor of P450 2D6.
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Serotonergic Drugs
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see
BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
considering the use of nortriptyline hydrochloride in a child or adolescent must balance
the potential risks with the clinical need.
Geriatric Use
Clinical studies of Pamelor did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other
reported clinical experience indicates that, as with other tricyclic antidepressants,
hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes)
are observed very rarely in geriatric patients and deaths associated with cholestatic liver
damage have been reported in isolated instances. Cardiovascular function, particularly
arrhythmias and fluctuations in blood pressure, should be monitored. There have also
been reports of confusional states following tricyclic antidepressant administration in the
elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10
hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic
antidepressants, dose selection for an elderly patient should usually be limited to the
smallest effective total daily dose (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Note – Included in the following list are a few adverse reactions that have not been
reported with this specific drug. However, the pharmacologic similarities among the
tricyclic antidepressant drugs require that each of the reactions be considered when
nortriptyline is administered.
Cardiovascular – Hypotension, hypertension, tachycardia, palpitation, myocardial
infarction, arrhythmias, heart block, stroke.
Psychiatric – Confusional states (especially in the elderly) with hallucinations,
disorientation, delusions; anxiety, restlessness, agitation; insomnia, panic, nightmares;
hypomania; exacerbation of psychosis.
Neurologic – Numbness, tingling, paresthesias of extremities; incoordination, ataxia,
tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alteration in EEG
patterns; tinnitus.
Anticholinergic – Dry mouth and, rarely, associated sublingual adenitis; blurred vision,
disturbance of accommodation, mydriasis; constipation, paralytic ileus; urinary retention,
delayed micturition, dilation of the urinary tract.
Allergic – Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive
exposure to sunlight); edema (general or of face and tongue), drug fever, cross-
sensitivity with other tricyclic drugs.
Hematologic – Bone marrow depression, including agranulocytosis; eosinophilia;
purpura; thrombocytopenia.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Gastrointestinal – Nausea and vomiting, anorexia, epigastric distress, diarrhea,
peculiar taste, stomatitis, abdominal cramps, blacktongue.
Endocrine – Gynecomastia in the male, breast enlargement and galactorrhea in the
female; increased or decreased libido, impotence; testicular swelling; elevation or
depression of blood sugar levels; syndrome of inappropriate ADH (antidiuretic hormone)
secretion.
Other – Jaundice (simulating obstructive), altered liver function; weight gain or loss;
perspiration; flushing; urinary frequency, nocturia; drowsiness, dizziness, weakness,
fatigue; headache; parotid swelling; alopecia.
Withdrawal Symptoms – Though these are not indicative of addiction, abrupt
cessation of treatment after prolonged therapy may produce nausea, headache, and
malaise.
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion
(including alcohol) is common in deliberate tricyclic antidepressant overdose. As the
management is complex and changing, it is recommended that the physician contact a
poison control center for current information on treatment. Signs and symptoms of
toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital
monitoring is required as soon as possible.
Manifestations
Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension,
shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression,
including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are
clinically significant indicators of tricyclic antidepressant toxicity.
Other signs of overdose may include: confusion, restlessness, disturbed concentration,
transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor,
drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the acute
symptoms listed under ADVERSE REACTIONS. There have been reports of patients
recovering from nortriptyline overdoses of up to 525 mg.
Management
General – Obtain an ECG and immediately initiate cardiac monitoring. Protect the
patient’s airway, establish an intravenous line and initiate gastric decontamination. A
minimum of six hours of observation with cardiac monitoring and observation for signs
of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction
blocks, and seizures is necessary. If signs of toxicity occur at any time during this
period, extended monitoring is required. There are case reports of patients succumbing
to fatal dysrhythmias late after overdose; these patients had clinical evidence of
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
significant poisoning prior to death and most received inadequate gastrointestinal
decontamination. Monitoring of plasma drug levels should not guide management of the
patient.
Gastrointestinal Decontamination – All patients suspected of tricyclic antidepressant
overdose should receive gastrointestinal decontamination. This should include large
volume gastric lavage followed by activated charcoal. If consciousness is impaired, the
airway should be secured prior to lavage. EMESIS IS CONTRAINDICATED.
Cardiovascular – A maximal limb-lead QRS duration of ≥0.10 seconds may be the best
indication of the severity of the overdose. Intravenous sodium bicarbonate should be
used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is
inadequate, hyperventilation may also be used. Concomitant use of hyperventilation
and sodium bicarbonate should be done with extreme caution, with frequent pH
monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias
unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine,
bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated
(e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion
may be beneficial in acute refractory cardiovascular instability in patients with acute
toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced
diuresis generally have been reported as ineffective in tricyclic antidepressant
poisoning.
CNS – In patients with CNS depression, early intubation is advised because of the
potential for abrupt deterioration. Seizures should be controlled with benzodiazepines,
or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).
Physostigmine is not recommended except to treat life-threatening symptoms that have
been unresponsive to other therapies, and then only in consultation with a poison
control center.
Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt
suicide by other means during the recovery phase. Psychiatric referral may be
appropriate.
Pediatric Management – The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact the local
poison control center for specific pediatric treatment.
DOSAGE AND ADMINISTRATION
Pamelor is not recommended for children.
Pamelor is administered orally in the form of capsules. Lower than usual dosages are
recommended for elderly patients and adolescents. Lower dosages are also
recommended for outpatients than for hospitalized patients who will be under close
supervision. The physician should initiate dosage at a low level and increase it
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gradually, noting carefully the clinical response and any evidence of intolerance.
Following remission, maintenance medication may be required for a longer period of
time at the lowest dose that will maintain remission.
If a patient develops minor side effects, the dosage should be reduced. The drug should
be discontinued promptly if adverse effects of a serious nature or allergic manifestations
occur.
Usual Adult Dose – 25 mg three or four times daily; dosage should begin at a low level
and be increased as required. As an alternate regimen, the total daily dosage may be
given once a day. When doses above 100 mg daily are administered, plasma levels of
nortriptyline should be monitored and maintained in the optimum range of 50 to
150 ng/mL. Doses above 150 mg/day are not recommended.
Elderly and Adolescent Patients – 30 to 50 mg/day, in divided doses, or the total daily
dosage may be given once a day.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended
to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat
psychiatric disorders and initiation of therapy with Pamelor. Conversely, at least 14 days
should be allowed after stopping Pamelor before starting an MAOI intended to treat
psychiatric disorders (see CONTRAINDICATIONS).
Use of Pamelor With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start Pamelor in a patient who is being treated with linezolid or intravenous
methylene blue because there is increased risk of serotonin syndrome. In a patient who
requires more urgent treatment of a psychiatric condition, other interventions, including
hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving Pamelor therapy may require urgent
treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential
benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the
risks of serotonin syndrome in a particular patient, Pamelor should be stopped promptly,
and linezolid or intravenous methylene blue can be administered. The patient should be
monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the
last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy
with Pamelor may be resumed 24 hours after the last dose of linezolid or intravenous
methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral
tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with
Pamelor is unclear. The clinician should, nevertheless, be aware of the possibility of
emergent symptoms of serotonin syndrome with such use (see WARNINGS).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Pamelor™ (nortriptyline HCl) Capsules USP
Pamelor™ (nortriptyline HCl) Capsules USP, equivalent to 10 mg, 25 mg, 50 mg, and
75 mg base, are available as follows:
10 mg: Light orange opaque cap printed “
PAMELOR 10 mg” in black and white
opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9910-03
25 mg: Light orange opaque cap printed “
PAMELOR 25 mg” in black and white
opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9911-03
50 mg: White opaque cap printed “
PAMELOR 50 mg” in black and white opaque
body printed “M” in black.
Bottles of 30 ............ NDC 0406-9912-03
75 mg: Light orange opaque cap printed “
PAMELOR 75 mg” in black and light
orange opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9913-03
Store and Dispense
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in tight container (USP) with a child-resistant closure.
Pamelor and M are trademarks of Mallinckrodt LLC.
Manufactured by:
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Medication Guide – Pamelor™ (nortriptyline HCl) Capsules USP
Antidepressant Medicines, Depression and other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s
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For current labeling information, please visit https://www.fda.gov/drugsatfda
antidepressant medicine. This Medication Guide is only about the risk of suicidal
thoughts and actions with antidepressant medicines. Talk to your, or your family
member’s, healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant
medicines, depression and other serious mental illnesses, and suicidal thoughts
or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes
of suicidal thoughts and actions. Some people may have a particularly high
risk of having suicidal thoughts or actions. These include people who have (or
have a family history of) bipolar illness (also called manic-depressive illness) or
suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself
or a family member?
• Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call a healthcare provider right away if you or your family member has any of
the following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
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• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
Visual problems
• eye pain
• changes in vision
• swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an eye
examination to see if you are at risk and receive preventative treatment if you are.
Who should not take Pamelor?
Do not take Pamelor if you:
• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
o Do not take an MAOI within 2 weeks of stopping Pamelor unless directed to
do so by your physician.
o Do not start Pamelor if you stopped taking an MAOI in the last 2 weeks
unless directed to do so by your physician.
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It
is important to discuss all the risks of treating depression and also the risks of not
treating it. Patients and their families or other caregivers should discuss all treatment
choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider
about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show
the healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for
use in children. Talk to your child’s healthcare provider for more information.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Page 15 of 16
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pamelor is a trademark of Mallinckrodt LLC.
Manufactured by:
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Rev 05/2014 company logo
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018013s062lbl.pdf', 'application_number': 18013, 'submission_type': 'SUPPL ', 'submission_number': 62}
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Sodium Chloride Injection, USP
in VIAFLEX Plastic Container
Description
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution
for fluid and electrolyte replenishment in single dose containers for
intravenous administration. It contains no antimicrobial agents.
The pH is 5.0 (4.5 to 7.0). Composition, osmolarity, and ionic
concentration are shown below:
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium
Chloride, USP (NaCl) with an osmolarity of 154 mOsmol/L (calc).
It contains 77 mEq/L sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride,
USP (NaCl) with an osmolarity of 308 mOsmol/L (calc). It contains
154 mEq/L sodium and 154 mEq/L chloride.
The VIAFLEX plastic container is fabricated from a specially formulated
polyvinyl chloride (PL 146 Plastic). The amount of water that can
permeate from inside the container into the overwrap is insufficient to
affect the solution significantly. Solutions in contact with the plastic
container can leach out certain of its chemical components in very small
amounts within the expiration period, e.g., di-2-ethylhexyl phthalate
(DEHP), up to 5 parts per million. However, the safety of the plastic has
been confirmed in tests in animals according to USP biological tests for
plastic containers as well as by tissue culture toxicity studies.
Clinical Pharmacology
Sodium Chloride Injection, USP has value as a source of water and
electrolytes. It is capable of inducing diuresis depending on the clinical
condition of the patient.
Indications and Usage
Sodium Chloride Injection, USP is indicated as a source of water
and electrolytes.
0.9% Sodium Chloride Injection, USP is also indicated for use as
a priming solution in hemodialysis procedures.
Contraindications
None known.
Warnings
Sodium Chloride Injection, USP should be used with great care, if at all,
in patients with congestive heart failure, severe renal insufficiency, and
in clinical states in which there exists edema with sodium retention.
The intravenous administration of Sodium Chloride Injection, USP can
cause fluid and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states, or
pulmonary edema. The risk of dilutive states is inversely proportional to
the electrolyte concentration of the injections. The risk of solute
overload causing congested states with peripheral and pulmonary edema
is directly proportional to the electrolyte concentrations of the injections.
In patients with diminished renal function, administration of Sodium
Chloride Injection, USP may result in sodium retention.
Precautions
Clinical evaluation and periodic laboratory determinations are necessary
to monitor changes in fluid balance, electrolyte concentrations, and acid
base balance during prolonged parenteral therapy or whenever the
condition of the patient warrants such evaluation.
Caution must be exercised in the administration of Sodium Chloride
Injection, USP to patients receiving corticosteroids or corticotropin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies have not been performed with Sodium Chloride Injection, USP
to evaluate the potential for carcinogenesis, mutagenesis or impairment
of fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been
conducted with Sodium Chloride Injection, USP. It is also not known
whether Sodium Chloride Injection, USP can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity.
Sodium Chloride Injection, USP should be given to a pregnant woman
only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be
exercised when Sodium Chloride Injection, USP is administered to
a nursing mother.
Pediatric Use
Safety and effectiveness of Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well
controlled trials, however, the use of sodium chloride solutions in
the pediatric population is referenced in the medical literature.
The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include
sufficient numbers of subjects aged 65 and over to determine whether
they respond differently from other younger subjects. Other reported
clinical experience has not identified differences in responses between
the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the
risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection,
and it may be useful to monitor renal function.
Do not administer unless solution is clear and seal is intact.
Adverse Reactions
Reactions which may occur because of the solution or the technique of
administration include febrile response, infection at the site of injection,
venous thrombosis or phlebitis extending from the site of injection,
extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the
patient, institute appropriate therapeutic countermeasures and save the
remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight
and clinical condition of the patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration whenever solution and
container permit.
All injections in VIAFLEX plastic containers are intended for intravenous
administration using sterile equipment.
07-19-47-261
*BAR CODE POSITION ONLY
071947261
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Baxter Healthcare Corporation
07-19-47-261
Deerfield, IL 60015 USA
Rev. March 2005
Printed in USA
Baxter, VIAFLEX and PL 146 are trademarks of
Baxter International Inc.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used.
Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use
aseptic technique. Mix thoroughly when additives have been
introduced. Do not store solutions containing additives.
How Supplied
The available sizes of each injection in VIAFLEX plastic containers
are shown below:
Code
Size (mL)
NDC
Product Name
2B1313
500
0338-0043-03
0.45% Sodium Chloride
2B1314
1000
0338-0043-04
Injection, USP
2B1355
100
0338-1452-48
2B1356
250
0338-1452-02
2B1300
25 Quad pack
0338-0049-10
0.9% Sodium Chloride
Injection, USP
50
2B1306
Single pack
0338-0049-41
2B1301
Quad pack
0338-0049-11
2B1308
Multi pack
0338-0049-31
100
2B1307
Single pack
0338-0049-48
2B1302
Quad pack
0338-0049-18
2B1309
Multi pack
0338-0049-38
2B1321
150
0338-0049-01
2B1322
250
0338-0049-02
2B1323
500
0338-0049-03
2B1324
1000
0338-0049-04
Exposure of pharmaceutical products to heat should be minimized.
Avoid excessive heat. It is recommended the product be stored at
room temperature (25°C/77°F); brief exposure up to 40°C (104°F)
does not adversely affect the product.
Directions for use of VIAFLEX plastic container
WARNING: Do not use plastic containers in series connections.
Such use could result in air embolism due to residual air being drawn
from the primary container before administration of the fluid from the
secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container.
Some opacity of the plastic due to moisture absorption during the
sterilization process may be observed. This is normal and does not
affect the solution quality or safety. The opacity will diminish gradually.
Check for minute leaks by squeezing inner bag firmly. If leaks are
found, discard solution as sterility may be impaired. If supplemental
medication is desired, follow directions below.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions
accompanying set.
To Add Medication
WARNING: Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable
medication port and inject.
3. Mix solution and medication thoroughly. For high density
medication such as potassium chloride, squeeze ports while ports
are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable
medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the
upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
*BAR CODE POSITION ONLY
071947261
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018016s056lbl.pdf', 'application_number': 18016, 'submission_type': 'SUPPL ', 'submission_number': 56}
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Pamelor™
(nortriptyline HCl) capsules USP
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term
studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of nortriptyline hydrochloride or any other
antidepressant in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24;
there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately
and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Nortriptyline hydrochloride
is not approved for use in pediatric patients (see WARNINGS, Clinical Worsening
and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS,
Pediatric Use).
DESCRIPTION
Pamelor™
(nortriptyline
HCl)
is
1-propanamine,
3-(10,11-dihydro-5H
dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-, hydrochloride.
The structural formula is as follows: structural formula
C19H21N•HCl
MW = 299.84
10 mg, 25 mg, 50 mg, and 75 mg Capsules
Active Ingredient: nortriptyline hydrochloride USP.
10 mg, 25 mg, and 75 mg Capsules
Inactive Ingredients: D&C Yellow #10, FD&C Yellow #6, gelatin, silicone fluid, starch,
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and titanium dioxide.
50 mg Capsules
Inactive Ingredients: gelatin, silicone fluid, starch, and titanium dioxide.
CLINICAL PHARMACOLOGY
The mechanism of mood elevation by tricyclic antidepressants is at present unknown.
Pamelor is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse
agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor
effect of norepinephrine but blocks the pressor response of phenethylamine. Studies
suggest that Pamelor interferes with the transport, release, and storage of
catecholamines. Operant conditioning techniques in rats and pigeons suggest that
Pamelor has a combination of stimulant and depressant properties.
INDICATIONS AND USAGE
Pamelor™ (nortriptyline HCl) is indicated for the relief of symptoms of depression.
Endogenous depressions are more likely to be alleviated than are other depressive
states.
CONTRAINDICATIONS
Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with Pamelor or within 14 days
of stopping treatment with Pamelor is contraindicated because of an increased risk of
serotonin syndrome. The use of Pamelor within 14 days of stopping an MAOI intended
to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE
AND ADMINISTRATION).
Starting Pamelor in a patient who is being treated with MAOIs such as linezolid or
intravenous methylene blue is also contraindicated because of an increased risk of
serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Hypersensitivity to Tricyclic Antidepressants
Cross-sensitivity between Pamelor and other dibenzazepines is a possibility.
Myocardial Infarction
Pamelor is contraindicated during the acute recovery period after myocardial infarction.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation and
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behavior (suicidality) or unusual changes in behavior, whether or not they are taking
antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-
standing concern, however, that antidepressants may have a role in inducing worsening
of depression and the emergence of suicidality in certain patients during the early
phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
(ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction
with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders
included a total of 295 short-term trials (median duration of 2 months) of 11
antidepressant drugs in over 77,000 patients. There was considerable variation in risk of
suicidality among drugs, but a tendency toward an increase in the younger patients for
almost all drugs studied. There were differences in absolute risk of suicidality across the
different indications, with the highest incidence in MDD. The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per
1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Increases Compared to Placebo
<18
18-24
14 additional cases
5 additional cases
Decreases Compared to Placebo
25-64
≥65
1 fewer case
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond
several months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants can delay
the recurrence of depression.
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All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of a
course of drug therapy, or at times of dose changes, either increases or
decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and
mania, have been reported in adult and pediatric patients being treated with
antidepressants for major depressive disorder as well as for other indications, both
psychiatric and nonpsychiatric. Although a causal link between the emergence of such
symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who
are experiencing emergent suicidality or symptoms that might be precursors to
worsening depression or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of
agitation, irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report such
symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for nortriptyline
hydrochloride should be written for the smallest quantity of capsules consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder – A major depressive episode may be the
initial presentation of bipolar disorder. It is generally believed (though not established in
controlled trials) that treating such an episode with an antidepressant alone may
increase the likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an antidepressant,
patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that nortriptyline hydrochloride is not approved for use in treating bipolar
depression.
Patients with cardiovascular disease should be given Pamelor only under close
supervision because of the tendency of the drug to produce sinus tachycardia and to
prolong the conduction time. Myocardial infarction, arrhythmia, and strokes have
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occurred. The antihypertensive action of guanethidine and similar agents may be
blocked. Because of its anticholinergic activity, Pamelor should be used with great
caution in patients who have a history of urinary retention. Patients with a history of
seizures should be followed closely when Pamelor is administered, inasmuch as this
drug is known to lower the convulsive threshold. Great care is required if Pamelor is
given to hyperthyroid patients or to those receiving thyroid medication, since cardiac
arrhythmias may develop.
Pamelor may impair the mental and/or physical abilities required for the performance of
hazardous tasks, such as operating machinery or driving a car; therefore, the patient
should be warned accordingly.
Excessive consumption of alcohol in combination with nortriptyline therapy may have a
potentiating effect, which may lead to the danger of increased suicidal attempts or
overdosage, especially in patients with histories of emotional disturbances or suicidal
ideation.
The concomitant administration of quinidine and nortriptyline may result in a significantly
longer plasma half-life, higher AUC, and lower clearance of nortriptyline.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported
with SNRIs and SSRIs, including Pamelor, alone but particularly with concomitant use
of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair
metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g.,
tremor,
rigidity,
myoclonus,
hyperreflexia,
incoordination),
seizures,
and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be
monitored for the emergence of serotonin syndrome.
The concomitant use of Pamelor with MAOIs intended to treat psychiatric disorders is
contraindicated. Pamelor should also not be started in a patient who is being treated
with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene
blue that provided information on the route of administration involved intravenous
administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the
administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a patient
taking Pamelor. Pamelor should be discontinued before initiating treatment with the
MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
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If concomitant use of Pamelor with other serotonergic drugs, including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort
is clinically warranted, patients should be made aware of a potential increased risk for
serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Pamelor and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic
treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including
Pamelor may trigger an angle-closure attack in a patient with anatomically narrow
angles who does not have a patent iridectomy.
Use in Pregnancy
Safe use of Pamelor during pregnancy and lactation has not been established;
therefore, when the drug is administered to pregnant patients, nursing mothers, or
women of childbearing potential, the potential benefits must be weighed against the
possible hazards. Animal reproduction studies have yielded inconclusive results.
PRECAUTIONS
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with nortriptyline
hydrochloride and should counsel them in its appropriate use. A patient Medication
Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness,
and Suicidal Thoughts or Actions” is available for nortriptyline hydrochloride. The
prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its
contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete
text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if
these occur while taking nortriptyline hydrochloride.
Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient’s prescriber
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or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
The use of Pamelor in schizophrenic patients may result in an exacerbation of the
psychosis or may activate latent schizophrenic symptoms. If the drug is given to
overactive or agitated patients, increased anxiety and agitation may occur. In manic-
depressive patients, Pamelor may cause symptoms of the manic phase to emerge.
Troublesome patient hostility may be aroused by the use of Pamelor. Epileptiform
seizures may accompany its administration, as is true of other drugs of its class.
When it is essential, the drug may be administered with electroconvulsive therapy,
although the hazards may be increased. Discontinue the drug for several days, if
possible, prior to elective surgery.
The possibility of a suicidal attempt by a depressed patient remains after the initiation of
treatment; in this regard, it is important that the least possible quantity of drug be
dispensed at any given time.
Both elevation and lowering of blood sugar levels have been reported.
Patients should be advised that taking Pamelor can cause mild pupillary dilation, which
in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre
existing glaucoma is almost always open-angle glaucoma because angle-closure
glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle
glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be
examined to determine whether they are susceptible to angle closure, and have a
prophylactic procedure (e.g., iridectomy), if they are susceptible.
Drug Interactions
Administration of reserpine during therapy with a tricyclic antidepressant has been
shown to produce a “stimulating” effect in some depressed patients.
Close supervision and careful adjustment of the dosage are required when Pamelor is
used with other anticholinergic drugs and sympathomimetic drugs.
Concurrent administration of cimetidine and tricyclic antidepressants can produce
clinically significant increases in the plasma concentrations of the tricyclic
antidepressant. The patient should be informed that the response to alcohol may be
exaggerated.
A case of significant hypoglycemia has been reported in a type II diabetic patient
maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline
(125 mg/day).
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Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the
Caucasian population (about 7% to 10% of Caucasians are so called “poor
metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of tricyclic
antidepressants (TCAs) when given usual doses. Depending on the fraction of drug
metabolized by P450 2D6, the increase in plasma concentration may be small, or quite
large (8 fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal
metabolizers resemble poor metabolizers. An individual who is stable on a given dose
of TCA may become abruptly toxic when given one of these inhibiting drugs as
concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are
not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for
P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C
antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake
inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they
may vary in the extent of inhibition. The extent to which SSRI TCA interactions may
pose clinical problems will depend on the degree of inhibition and the pharmacokinetics
of the SSRI involved. Nevertheless, caution is indicated in the co-administration of
TCAs with any of the SSRIs and also in switching from one class to the other. Of
particular importance, sufficient time must elapse before initiating TCA treatment in a
patient being withdrawn from fluoxetine, given the long half-life of the parent and active
metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome
P450 2D6 may require lower doses than usually prescribed for either the tricyclic
antidepressant or the other drug. Furthermore, whenever one of these other drugs is
withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be
required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be
co-administered with another drug known to be an inhibitor of P450 2D6.
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Serotonergic Drugs
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see
BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone
considering the use of nortriptyline hydrochloride in a child or adolescent must balance
the potential risks with the clinical need.
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Geriatric Use
Clinical studies of Pamelor did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other
reported clinical experience indicates that, as with other tricyclic antidepressants,
hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes)
are observed very rarely in geriatric patients and deaths associated with cholestatic liver
damage have been reported in isolated instances. Cardiovascular function, particularly
arrhythmias and fluctuations in blood pressure, should be monitored. There have also
been reports of confusional states following tricyclic antidepressant administration in the
elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10
hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic
antidepressants, dose selection for an elderly patient should usually be limited to the
smallest effective total daily dose (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Note – Included in the following list are a few adverse reactions that have not been
reported with this specific drug. However, the pharmacologic similarities among the
tricyclic antidepressant drugs require that each of the reactions be considered when
nortriptyline is administered.
Cardiovascular – Hypotension, hypertension, tachycardia, palpitation, myocardial
infarction, arrhythmias, heart block, stroke.
Psychiatric – Confusional states (especially in the elderly) with hallucinations,
disorientation, delusions; anxiety, restlessness, agitation; insomnia, panic, nightmares;
hypomania; exacerbation of psychosis.
Neurologic – Numbness, tingling, paresthesias of extremities; incoordination, ataxia,
tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alteration in EEG
patterns; tinnitus.
Anticholinergic – Dry mouth and, rarely, associated sublingual adenitis; blurred vision,
disturbance of accommodation, mydriasis; constipation, paralytic ileus; urinary retention,
delayed micturition, dilation of the urinary tract.
Allergic – Skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive
exposure to sunlight); edema (general or of face and tongue), drug fever, cross-
sensitivity with other tricyclic drugs.
Hematologic – Bone marrow depression, including agranulocytosis; eosinophilia;
purpura; thrombocytopenia.
Gastrointestinal – Nausea and vomiting, anorexia, epigastric distress, diarrhea,
peculiar taste, stomatitis, abdominal cramps, blacktongue.
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Endocrine – Gynecomastia in the male, breast enlargement and galactorrhea in the
female; increased or decreased libido, impotence; testicular swelling; elevation or
depression of blood sugar levels; syndrome of inappropriate ADH (antidiuretic hormone)
secretion.
Other – Jaundice (simulating obstructive), altered liver function; weight gain or loss;
perspiration; flushing; urinary frequency, nocturia; drowsiness, dizziness, weakness,
fatigue; headache; parotid swelling; alopecia.
Withdrawal Symptoms – Though these are not indicative of addiction, abrupt
cessation of treatment after prolonged therapy may produce nausea, headache, and
malaise.
Postmarketing Experience
The following adverse drug reaction has been reported during post-approval use of
Pamelor. Because this reaction is reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate frequency.
Eye Disorders – angle-closure glaucoma
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion
(including alcohol) is common in deliberate tricyclic antidepressant overdose. As the
management is complex and changing, it is recommended that the physician contact a
poison control center for current information on treatment. Signs and symptoms of
toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital
monitoring is required as soon as possible.
Manifestations
Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension,
shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression,
including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are
clinically significant indicators of tricyclic antidepressant toxicity.
Other signs of overdose may include: confusion, restlessness, disturbed concentration,
transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor,
drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the acute
symptoms listed under ADVERSE REACTIONS. There have been reports of patients
recovering from nortriptyline overdoses of up to 525 mg.
Management
General – Obtain an ECG and immediately initiate cardiac monitoring. Protect the
patient’s airway, establish an intravenous line and initiate gastric decontamination. A
minimum of six hours of observation with cardiac monitoring and observation for signs
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of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction
blocks, and seizures is necessary. If signs of toxicity occur at any time during this
period, extended monitoring is required. There are case reports of patients succumbing
to fatal dysrhythmias late after overdose; these patients had clinical evidence of
significant poisoning prior to death and most received inadequate gastrointestinal
decontamination. Monitoring of plasma drug levels should not guide management of the
patient.
Gastrointestinal Decontamination – All patients suspected of tricyclic antidepressant
overdose should receive gastrointestinal decontamination. This should include large
volume gastric lavage followed by activated charcoal. If consciousness is impaired, the
airway should be secured prior to lavage. EMESIS IS CONTRAINDICATED.
Cardiovascular – A maximal limb-lead QRS duration of ≥0.10 seconds may be the best
indication of the severity of the overdose. Intravenous sodium bicarbonate should be
used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is
inadequate, hyperventilation may also be used. Concomitant use of hyperventilation
and sodium bicarbonate should be done with extreme caution, with frequent pH
monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias
unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine,
bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated
(e.g., quinidine, disopyramide, and procainamide). In rare instances, hemoperfusion
may be beneficial in acute refractory cardiovascular instability in patients with acute
toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced
diuresis generally have been reported as ineffective in tricyclic antidepressant
poisoning.
CNS – In patients with CNS depression, early intubation is advised because of the
potential for abrupt deterioration. Seizures should be controlled with benzodiazepines,
or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).
Physostigmine is not recommended except to treat life-threatening symptoms that have
been unresponsive to other therapies, and then only in consultation with a poison
control center.
Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt
suicide by other means during the recovery phase. Psychiatric referral may be
appropriate.
Pediatric Management – The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact the local
poison control center for specific pediatric treatment.
DOSAGE AND ADMINISTRATION
Pamelor is not recommended for children.
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Pamelor is administered orally in the form of capsules. Lower than usual dosages are
recommended for elderly patients and adolescents. Lower dosages are also
recommended for outpatients than for hospitalized patients who will be under close
supervision. The physician should initiate dosage at a low level and increase it
gradually, noting carefully the clinical response and any evidence of intolerance.
Following remission, maintenance medication may be required for a longer period of
time at the lowest dose that will maintain remission.
If a patient develops minor side effects, the dosage should be reduced. The drug should
be discontinued promptly if adverse effects of a serious nature or allergic manifestations
occur.
Usual Adult Dose – 25 mg three or four times daily; dosage should begin at a low level
and be increased as required. As an alternate regimen, the total daily dosage may be
given once a day. When doses above 100 mg daily are administered, plasma levels of
nortriptyline should be monitored and maintained in the optimum range of 50 to
150 ng/mL. Doses above 150 mg/day are not recommended.
Elderly and Adolescent Patients – 30 to 50 mg/day, in divided doses, or the total daily
dosage may be given once a day.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended
to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat
psychiatric disorders and initiation of therapy with Pamelor. Conversely, at least 14 days
should be allowed after stopping Pamelor before starting an MAOI intended to treat
psychiatric disorders (see CONTRAINDICATIONS).
Use of Pamelor With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start Pamelor in a patient who is being treated with linezolid or intravenous
methylene blue because there is increased risk of serotonin syndrome. In a patient who
requires more urgent treatment of a psychiatric condition, other interventions, including
hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving Pamelor therapy may require urgent
treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential
benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the
risks of serotonin syndrome in a particular patient, Pamelor should be stopped promptly,
and linezolid or intravenous methylene blue can be administered. The patient should be
monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the
last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy
with Pamelor may be resumed 24 hours after the last dose of linezolid or intravenous
methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral
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tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with
Pamelor is unclear. The clinician should, nevertheless, be aware of the possibility of
emergent symptoms of serotonin syndrome with such use (see WARNINGS).
HOW SUPPLIED
Pamelor™ (nortriptyline HCl) Capsules USP
Pamelor™ (nortriptyline HCl) Capsules USP, equivalent to 10 mg, 25 mg, 50 mg, and
75 mg base, are available as follows:
10 mg: Light orange opaque cap printed “
PAMELOR 10 mg” in black and white
opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9910-03
25 mg: Light orange opaque cap printed “
PAMELOR 25 mg” in black and white
opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9911-03
50 mg: White opaque cap printed “
PAMELOR 50 mg” in black and white opaque
body printed “M” in black.
Bottles of 30 ............ NDC 0406-9912-03
75 mg: Light orange opaque cap printed “
PAMELOR 75 mg” in black and light
orange opaque body printed “M” in black.
Bottles of 30 ............ NDC 0406-9913-03
Store and Dispense
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in tight container (USP) with a child-resistant closure.
Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo, M and other
brands are trademarks of a Mallinckrodt company.
© 2014 Mallinckrodt.
Manufactured by:
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Medication Guide – Pamelor™ (nortriptyline HCl) capsules USP
Page 13 of 16
06/2014.2
Reference ID: 3600048
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Antidepressant Medicines, Depression and other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s
antidepressant medicine. This Medication Guide is only about the risk of suicidal
thoughts and actions with antidepressant medicines. Talk to your, or your family
member’s, healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant
medicines, depression and other serious mental illnesses, and suicidal thoughts
or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes
of suicidal thoughts and actions. Some people may have a particularly high
risk of having suicidal thoughts or actions. These include people who have (or
have a family history of) bipolar illness (also called manic-depressive illness) or
suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself
or a family member?
• Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call a healthcare provider right away if you or your family member has any of
the following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
Page 14 of 16
06/2014.2
Reference ID: 3600048
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
Visual problems
• eye pain
• changes in vision
• swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an eye
examination to see if you are at risk and receive preventative treatment if you are.
Who should not take Pamelor?
Do not take Pamelor if you:
• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
o Do not take an MAOI within 2 weeks of stopping Pamelor unless directed to
do so by your physician.
o Do not start Pamelor if you stopped taking an MAOI in the last 2 weeks
unless directed to do so by your physician.
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It
is important to discuss all the risks of treating depression and also the risks of not
treating it. Patients and their families or other caregivers should discuss all treatment
choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider
about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show
the healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for
use in children. Talk to your child’s healthcare provider for more information.
Page 15 of 16
06/2014.2
Reference ID: 3600048
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other
brands are trademarks of a Mallinckrodt company.
© 2014 Mallinckrodt.
Manufactured by:
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Rev 06/2014 company logo
Page 16 of 16
06/2014.2
Reference ID: 3600048
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:27.975823
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018013s063lbl.pdf', 'application_number': 18013, 'submission_type': 'SUPPL ', 'submission_number': 63}
|
11,118
|
07-19-69-742
Baxter
Sodium Chloride Injection, USP
in AVIVA Plastic Container
DESCRIPTION
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment in single dose containers for intravenous administration. It
contains no antimicrobial agents. The nominal pH is 5.5 (4.5 to 7.0). Composition,
osmolarity, and ionic concentration are shown below:
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl)
with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L
chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl)
with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154
mEq/L chloride.
The flexible container is made with non-latex plastic materials specially designed for a
wide range of parenteral drugs including those requiring delivery in containers made of
polyolefins or polypropylene. For example, the AVIVA container system is compatible
with and appropriate for use in the admixture and administration of paclitaxel. In
addition, the AVIVA container system is compatible with and appropriate for use in the
admixture and administration of all drugs deemed compatible with existing polyvinyl
chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological
evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP)
testing for plastic containers. These tests confirm the biological safety of the container
system.
The flexible container is a closed system, and air is prefilled in the container to facilitate
drainage. The container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an
intravenous administration set and the other port has a medication site for addition of
1
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
supplemental medication (See Directions for Use). The primary function of the overwrap
is to protect the container from the physical environment.
CLINICAL PHARMACOLOGY
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is
capable of inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in
hemodialysis procedures.
CONTRAINDICATIONS
None known.
WARNINGS
Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there
exists edema with sodium retention.
In patients with diminished renal function, administration of Sodium Chloride Injection,
USP may result in sodium retention.
PRECAUTIONS
General
Do not connect flexible plastic containers of intravenous solutions in series connections.
Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
Reference ID: 3370968
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor
changes in fluid balance, electrolyte concentrations, and acid base balance during
prolonged parenteral therapy or whenever the condition of the patient warrants such
evaluation.
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food
interactions with Sodium Chloride Injection, USP.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Animal reproduction studies have not been conducted with Sodium Chloride Injection,
USP. It is also not known whether Sodium Chloride Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium
Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when Sodium Chloride Injection,
USP is administered to a nursing woman.
3
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical
practice.
Plasma electrolyte concentrations should be closely monitored in the pediatric population
as this population may have impaired ability to regulate fluids and electrolytes.
The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with
the non-osmotic secretion of ADH may result in hyponatremia in patients with acute
volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma,
cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is
considered a medical emergency.
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in the responses
between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function and of concomitant
disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
Reactions which may occur because of the solution or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis or phlebitis
extending from the site of injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures and save the remainder of the fluid for
examination if deemed necessary.
In addition to the above listed adverse reactions, the following has been reported for
0.45% Sodium Chloride Injection, USP (see Pediatric Use section).
Reference ID: 3370968
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
- Hyponatremia
DOSAGE AND ADMINISTRATION
As directed by a physician. Dosage is dependent upon the age, weight and clinical
condition of the patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Do not
administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration
using sterile equipment.
Additives may be incompatible. Complete information is not available. Those additives
known to be incompatible should not be used. Consult with pharmacist, if available. If, in
the informed judgment of the physician, it is deemed advisable to introduce additives, use
aseptic technique. Mix thoroughly when additives have been introduced. Do not store
solutions containing additives.
HOW SUPPLIED
The available sizes of each injection in AVIVA plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
6E1313
500
0338-6333-03
0.45% Sodium Chloride
6E1314
1000
0338-6333-04
Injection, USP
6E1356
250
0338-6333-02
6E1322
250
0338-6304-02
0.9% Sodium Chloride
6E1323
500
0338-6304-03
Injection, USP
6E1324
1000
0338-6304-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C/77°F); brief exposure
up to 40°C (104°F) does not adversely affect the product.
DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some
opacity of the plastic due to moisture absorption during the sterilization process may be
Reference ID: 3370968
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
observed. This is normal and does not affect the solution quality or safety. The opacity
will diminish gradually. Check for minute leaks by squeezing inner bag firmly. If leaks
are found, discard solution as sterility may be impaired. If supplemental medication is
desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and
inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and
inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
6
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
071969742
07-19-69-742
Revised, September 2013
Baxter and AVIVA are trademarks of
Baxter International Inc.
For Product Information
1-800-933-0303
Reference ID: 3370968
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
07-19-69-741
Baxter
Sodium Chloride Injection, USP
in VIAFLEX Plastic Container
DESCRIPTION
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment in single dose containers for intravenous administration. It
contains no antimicrobial agents. The pH is 5.0 (4.5 to 7.0). Composition, osmolarity, and
ionic concentration are shown below:
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl)
with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L
chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl)
with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154
mEq/L chloride.
The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). The amount of water that can permeate from inside the
container into the overwrap is insufficient to affect the solution significantly. Solutions in
contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to
5 parts per million. However, the safety of the plastic has been confirmed in tests in
animals according to USP biological tests for plastic containers as well as by tissue
culture toxicity studies.
CLINICAL PHARMACOLOGY
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is
capable of inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in
hemodialysis procedures.
Reference ID: 3370968
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
None known.
WARNINGS
Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there
exists edema with sodium retention.
The intravenous administration of Sodium Chloride Injection, USP can cause fluid and/or
solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states, or pulmonary edema. The risk of dilutive states is
inversely proportional to the electrolyte concentration of the injections. The risk of solute
overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injections.
In patients with diminished renal function, administration of Sodium Chloride Injection,
USP may result in sodium retention.
PRECAUTIONS
General
Do not use plastic containers in series connections. Such use could result in air embolism
due to residual air being drawn from the primary container before administration of the
fluid from the secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor
changes in fluid balance, electrolyte concentrations, and acid base balance during
prolonged parenteral therapy or whenever the condition of the patient warrants such
evaluation.
Reference ID: 3370968
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies have not been performed with Sodium Chloride Injection, USP to evaluate the
potential for carcinogenesis, mutagenesis, or impairment of fertility.
Pregnancy:
Teratogenic Effects
Pregnancy Category C
Animal reproduction studies have not been conducted with Sodium Chloride Injection,
USP. It is also not known whether Sodium Chloride Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium
Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when Sodium Chloride Injection,
USP is administered to a nursing mother.
Pediatric Use
The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical
practice.
Plasma electrolyte concentrations should be closely monitored in the pediatric population
as this population may have impaired ability to regulate fluids and electrolytes.
The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with
the non-osmotic secretion of ADH may result in hyponatremia in patients with acute
volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma,
cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is
considered a medical emergency.
3
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function.
Do not administer unless solution is clear and seal is intact.
ADVERSE REACTIONS
Reactions which may occur because of the solution or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis or phlebitis
extending from the site of injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures and save the remainder of the fluid for
examination if deemed necessary.
In addition to the above listed adverse reactions the following has been reported for
0.45% Sodium Chloride Injection, USP (see Pediatric Use section):
- Hyponatremia
DOSAGE AND ADMINISTRATION
As directed by a physician. Dosage is dependent upon the age, weight and clinical
condition of the patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
All injections in VIAFLEX plastic containers are intended for intravenous administration
using sterile equipment.
Reference ID: 3370968
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Additives may be incompatible. Complete information is not available. Those additives
known to be incompatible should not be used. Consult with pharmacist, if available. If, in
the informed judgment of the physician, it is deemed advisable to introduce additives, use
aseptic technique. Mix thoroughly when additives have been introduced. Do not store
solutions containing additives.
HOW SUPPLIED
The available sizes of each injection in VIAFLEX plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
2B1313
500
0338-0043-03
0.45% Sodium Chloride
Injection, USP
2B1314
1000
0338-0043-04
2B1355
100
0338-1452-48
2B1356
250
0338-1452-02
2B1300
25 Quad Pack
0338-0049-10
0.9% Sodium Chloride
Injection, USP
50
2B1306
Single pack
0338-0049-41
2B1301
Quad pack
0338-0049-11
2B1308
Multi pack
0338-0049-31
100
2B1307
Single pack
0338-0049-48
2B1302
Quad pack
0338-0049-18
2B1309
Multi pack
0338-0049-38
2B1321
150
0338-0049-01
2B1322
250
0338-0049-02
2B1323
500
0338-0049-03
2B1324
1000
0338-0049-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C/77°F); brief exposure
up to 40°C (104°F) does not adversely affect the product.
5
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This
is normal and does not affect the solution quality or safety. The opacity will diminish
gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found,
discard solution as sterility may be impaired. If supplemental medication is desired,
follow directions below.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
WARNING
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
Reference ID: 3370968
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*BAR CODE POSITION ONLY
071969741
07-19-69-741
Rev. September 2013
BAXTER, VIAFLEX and PL 146 are trademarks of
Baxter International Inc.
7
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
07-19-69-768
Baxter
Ringer’s Injection, USP
in VIAFLEX Plastic Container
DESCRIPTION
Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no
antimicrobial agents. The pH may have been adjusted with sodium hydroxide.
Composition, osmolarity, pH and ionic concentration are shown in Table 1.
Table 1.
Size (mL)
Composition (g/L)
Osmolarity
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
Sodium Chloride, USP (NaCl)
Calcium Chloride, USP
(CaCl2-2H2 O)
Potassium Chloride, USP (KCl)
Sodium
Potassium
Calcium
Chloride
Ringer’s
Injection,
USP
500
8.6
0.33
0.3
309
5.5
(5.0 to 7.5)
147.5
4
4.5
156
1000
The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). The amount of water that can permeate from inside the
container into the overwrap is insufficient to affect the solution significantly. Solutions in
contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to
5 parts per million. However, the safety of the plastic has been confirmed in tests in
animals according to USP biological tests for plastic containers as well as by tissue
culture toxicity studies.
1
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Ringer’s Injection, USP is indicated as a source of water and electrolytes.
CONTRAINDICATIONS
None known
WARNINGS
Ringer’s Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there
exists edema with sodium retention.
Ringer’s Injection, USP should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium retention is
present.
Ringer’s Injection, USP should not be administered simultaneously with blood through
the same administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute
overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to
the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s Injection, USP may
result in sodium or potassium retention.
PRECAUTIONS
Do not use plastic containers in series connections. Such use could result in air embolism
due to residual air being drawn from the primary container before administration of the
fluid from the secondary container is completed.
2
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
Clinical evaluation and periodic laboratory determinations are necessary to monitor
changes in fluid balance, electrolyte concentrations, and acid base balance during
prolonged parenteral therapy or whenever the condition of the patient warrants such
evaluation.
Caution must be exercised in the administration of Ringer’s Injection, USP to patients
receiving corticosteroids or corticotropin.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Animal reproduction studies have not been conducted with Ringer’s Injection, USP. It is
also not known whether Ringer’s Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should
be given to a pregnant woman only if clearly needed.
Pediatric Use
The use of Ringer’s Injection, USP in pediatric patients is based on clinical practice.
Geriatric Use
Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the
elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
Do not administer unless solution is clear and seal is intact.
Reference ID: 3370968
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Reactions which may occur because of the solution or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis or phlebitis
extending from the site of injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures, and save the remainder of the fluid for
examination if deemed necessary.
DOSAGE AND ADMINISTRATION
As directed by a physician. Dosage is dependent upon the age, weight and clinical
condition of the patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
All injections in VIAFLEX plastic containers are intended for intravenous administration
using sterile equipment.
Additives may be incompatible. Complete information is not available. Those additives
known to be incompatible should not be used. Consult with pharmacist, if available. If, in
the informed judgment of the physician, it is deemed advisable to introduce additives, use
aseptic technique. Mix thoroughly when additives have been introduced. Do not store
solutions containing additives.
HOW SUPPLIED
Ringer’s Injection, USP in VIAFLEX plastic container is available as follows:
Code
Size (mL)
NDC
2B2303
500
0338-0105-03
2B2304
1000
0338-0105-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C); brief exposure up to
40°C does not adversely affect the product.
4
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This
is normal and does not affect the solution quality or safety. The opacity will diminish
gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found,
discard solution as sterility may be impaired. If supplemental medication is desired,
follow directions below.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
WARNING: Additives may be incompatible
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and
inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Reference ID: 3370968
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*BAR CODE POSITION ONLY
071969768
07-19-69-768
Revised September 2013
BAXTER, VIAFLEX AND PL 146 ARE
TRADEMARKS OF BAXTER INTERNATIONAL INC.
6
Reference ID: 3370968
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:28.529400
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016677s147,016693s096,018016s061lbl.pdf', 'application_number': 18016, 'submission_type': 'SUPPL ', 'submission_number': 61}
|
11,119
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Sodium Chloride Injection, USP
in AVIVA Plastic Container
DESCRIPTION
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment in single dose containers for intravenous administration. It
contains no antimicrobial agents. The nominal pH is 5.5 (4.5 to 7.0). Composition,
osmolarity, and ionic concentration are shown below:
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl)
and is hypotonic with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L
sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl)
with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154
mEq/L chloride.
The flexible container is made with non-latex plastic materials specially designed for a
wide range of parenteral drugs including those requiring delivery in containers made of
polyolefins or polypropylene. For example, the AVIVA container system is compatible
with and appropriate for use in the admixture and administration of paclitaxel. In
addition, the AVIVA container system is compatible with and appropriate for use in the
admixture and administration of all drugs deemed compatible with existing polyvinyl
chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological
evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP)
testing for plastic containers. These tests confirm the biological safety of the container
system.
The flexible container is a closed system, and air is prefilled in the container to facilitate
drainage. The container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an
intravenous administration set and the other port has a medication site for addition of
supplemental medication (See DIRECTIONS FOR USE). The primary function of the
overwrap is to protect the container from the physical environment.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is
capable of inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in
hemodialysis procedures.
CONTRAINDICATIONS
None known.
WARNINGS
Hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills,
urticaria, rash, and pruritus have been reported with 0.9% Sodium Chloride Injection,
USP and may occur with 0.45% Sodium Chloride Injection, USP.
Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction
develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic
countermeasures must be instituted as clinically indicated.
Depending on the volume and rate of infusion, the intravenous administration of Sodium
Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration/hypervolemia, congested states,
pulmonary edema, or acid-base imbalance. The risk of dilutive states is inversely
proportional to the electrolyte concentration of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to
the electrolyte concentrations of the injection.
Monitor changes in fluid balance, electrolyte concentrations, and acid base balance
during prolonged parenteral therapy or whenever the condition of the patient or the rate
of administration warrants such evaluation.
Administer with 0.9% Sodium Chloride Injection, USP with particular caution to patients
with or at risk for hypernatremia, hyperchloremia, or metabolic acidosis.
The infusion of solutions with 0.45% Sodium Chloride Injection, USP may result in
hyponatremia. Close clinical monitoring may be warranted. Hyponatremia can lead to
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
headache, nausea, seizures, lethargy, coma, cerebral edema and death. The risk for
hyponatremia is increased, for example, in children, elderly, women, postoperatively, in
persons with psychogenic polydipsia, and in patients treated with medications that
increase the risk of hyponatremia (such as certain antiepileptic and psychotropic
medications). The risk for developing hyponatremic encephalopathy is increased, for
example, in pediatric patients (≤16 years of age), women (in particular pre-menopausal
women), in patients with hypoxemia, and in patients with underlying central nervous
system disease. Acute symptomatic hyponatremic encephalopathy is considered a
medical emergency.
Administer Sodium Chloride Injection, USP with particular caution to patients with or at
risk for hypervolemia or with conditions that may cause sodium retention, fluid overload
and edema; such as patients with primary hyperaldosteronism, or secondary
hyperaldosteronism [e.g., associated with hypertension, congestive heart failure, liver
disease (including cirrhosis), renal disease (including renal artery stenosis,
nephrosclerosis) or pre-eclampsia]. Certain medications may increase risk of sodium and
fluid retention, see DRUG INTERACTIONS.
ADMINISTER Sodium Chloride Injection, USP with particular caution to patients with
severe renal impairment. In such patients, administration of Sodium Chloride Injection,
USP may result in sodium retention.
PRECAUTIONS
General
Do not connect flexible plastic containers in series in order to avoid air embolism due to
possible residual air contained in the primary container. Such use could result in air
embolism due to residual air being drawn from one container before administration of the
fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
Do not mix or administer 0.45% Sodium Chloride Injection, USP through the same
administration set with whole blood or cellular blood components.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rapid correction of hypo- and hypernatremia is potentially dangerous (risk of serious
neurologic complications). Dosage, rate, and duration of administration should be
determined by a physician experienced in intravenous fluid therapy.
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to
patients treated with drugs that may increase the risk of sodium and fluid retention, such
as corticosteroids.
Caution is advised in patients treated with lithium. Renal sodium and lithium clearance
may be decreased in the presence of hyponatremia. Administration of 0.45% Sodium
Chloride Injection, USP may result in increased lithium levels.
Renal sodium and lithium clearance may be increased during administration of 0.9%
Sodium Chloride Injection, USP. Administration of 0.9% Sodium Chloride Injection,
USP, may result in decreased lithium levels.
Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies with Sodium Chloride Injection, USP
in pregnant women and animal reproduction studies have not been conducted with this
drug. Therefore, it is not known whether Sodium Chloride Injection, USP can cause fetal
harm when administered to a pregnant woman. Sodium Chloride Injection, USP should
be given during pregnancy only if only if the potential benefit justifies the potential risk
to the fetus.
Nursing Mothers
It is not known whether this drug is present in human milk. Because many drugs are
present in human milk, caution should be exercised when Sodium Chloride Injection,
USP is administered to a nursing woman.
Pediatric Use
The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical
practice. (See DOSAGE AND ADMINISTRATION).
Plasma electrolyte concentrations should be closely monitored in the pediatric population
as this population may have impaired ability to regulate fluids and electrolytes.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with
the non-osmotic secretion of ADH may result in hyponatremia in patients with acute
volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma,
cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is
considered a medical emergency.
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in the responses
between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function and of concomitant
disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
Post-Marketing Adverse Reactions
The following adverse reactions have been identified during postapproval use of Sodium
Chloride Injection, USP. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
The following adverse reactions have been reported in the post-marketing experience
during use of 0.9% Sodium Chloride Injection, USP and include the following:
hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills,
urticaria, rash, pruritus.
Also reported are: infusion site reactions, such as infusion site erythema, injection site
streaking, burning sensation, and infusion site urticarial.
The following adverse reactions have not been reported with 0.9% Sodium Chloride
Injection, USP but may occur: hypernatremia, hyperchloremic metabolic acidosis, and
hyponatremia, which may be symptomatic.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hyponatremia has been reported for 0.45% Sodium Chloride Injection, USP (see
Pediatric Use section).
The following adverse reactions have not been reported with 0.45% Sodium Chloride
Injection, USP but may occur: hyperchloremic metabolic acidosis,
hypersensitivity/infusion reaction (including hypotension, pyrexia, tremor, chills,
urticaria, rash and pruritus), and infusion site reactions (such as infusion site erythema,
injection site streaking, burning sensation, infusion site urticaria).
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures and save the remainder of the fluid for
examination if deemed necessary.
OVERDOSAGE
Excessive administration of 0.45% Sodium Chloride Injection, USP may lead to hypo-
and hypernatremia, while excessive administration of 0.9% Sodium Chloride Injection,
USP may lead to hypernatremia. Both hypo- and hypernatremia can lead to CNS
manifestations, including seizures, coma, cerebral edema and death.
Excessive administration of Sodium Chloride Injection, USP may lead to sodium
overload (which can lead to central and/or peripheral edema).
When assessing an overdose, any additives in the solution must also be considered. The
effects of an overdose may require immediate medical attention and treatment.
DOSAGE AND ADMINISTRATION
All injections in AVIVA plastic containers are intended for intravenous administration
using sterile and nonpyrogenic equipment.
As directed by a physician. Dosage, rate, and duration of administration are to be
individualized and depend upon the indication for use, the patient’s age, weight, clinical
condition, concomitant treatment, and on the patient’s clinical and laboratory response to
treatment.
When other electrolytes or medicines are added to this solution, the dosage and the
infusion rate will also be dictated by the dose regimen of the additions.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Use of a
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
final filter is recommended during administration of all parenteral solutions, where
possible.
Do not administer unless solution is clear and seal is intact.
Additives may be incompatible with Sodium Chloride Injection, USP. As with all
parenteral solutions, compatibility of the additives with the solution must be assessed
before addition. Before adding a substance or medication, verify that it is soluble and/or
stable in water and that the pH range of Sodium Chloride Injection, USP is appropriate.
After addition, check for unexpected color changes and/or the appearance of precipitates,
insoluble complexes or crystals.
The instructions for use of the medication to be added and other relevant literature must
be consulted. Additives known or determined to be incompatible must not be used. When
introducing additives to Sodium Chloride Injection, USP, aseptic technique must be used.
Mix the solution thoroughly when additives have been introduced. Do not store solutions
containing additives.
After opening the container, the contents should be used immediately and should not be
stored for a subsequent infusion. Do not reconnect any partially used containers. Discard
any unused portion.
HOW SUPPLIED
The available sizes of each injection in AVIVA plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
6E1313
500
0338-6333-03
0.45% Sodium Chloride
6E1314
1000
0338-6333-04
Injection, USP
6E1356
250
0338-6333-02
6E1322
250
0338-6304-02
0.9% Sodium Chloride
6E1323
500
0338-6304-03
Injection, USP
6E1324
1000
0338-6304-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C/77°F); brief exposure
up to 40°C/104°F does not adversely affect the product.
DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER
For Information on Risk of Air Embolism – see PRECAUTIONS.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To Open
Tear overwrap down side at slit and remove solution container. Visually inspect the
container. If the outlet port protector is damaged, detached, or not present, discard
container as solution path sterility may be impaired. Some opacity of the plastic due to
moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check
for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as
sterility may be impaired. If supplemental medication is desired, follow directions below.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and
inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and
inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
Distributed in Canada by
Baxter Corporation
Mississauga, ON L5N 0C2
07-19-71-905
Revised, December 2014
Baxter and Aviva are trademarks of Baxter International Inc.
For Product Information
1-800-933-0303
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sodium Chloride Injection, USP
in VIAFLEX Plastic Container
DESCRIPTION
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment in single dose containers for intravenous administration. It
contains no antimicrobial agents. The nominal pH is 5.0 (4.5 to 7.0). Composition,
osmolarity, and ionic concentration are shown below:
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl)
and is hypotonic with an osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L
sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride, USP (NaCl)
with an osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154
mEq/L chloride.
The VIAFLEX plastic container is fabricated from a specially formulated
polyvinylchloride (PL 146 Plastic). The amount of water that can permeate from inside
the container into the overwrap is insufficient to affect the solution significantly.
Solutions in contact with the plastic container can leach out certain of its chemical
components in very small amounts within the expiration period, e.g., di-2-ethylhexyl
phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been
confirmed in tests in animals according to USP biological tests for plastic containers as
well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is
capable of inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in
hemodialysis procedures.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
None known.
WARNINGS
Hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills,
urticaria, rash, and pruritus have been reported with 0.9% Sodium Chloride Injection,
USP and may occur with 0.45% Sodium Chloride Injection, USP.
Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction
develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic
countermeasures must be instituted as clinically indicated.
Depending on the volume and rate of infusion, the intravenous administration of Sodium
Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration/hypervolemia, congested states,
pulmonary edema, or acid-base imbalance. The risk of dilutive states is inversely
proportional to the electrolyte concentration of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to
the electrolyte concentrations of the injection.
Monitor changes in fluid balance, electrolyte concentrations, and acid base balance
during prolonged parenteral therapy or whenever the condition of the patient or the rate
of administration warrants such evaluation.
Administer 0.9% Sodium Chloride Injection, USP with particular caution, to patients
with or at risk for hypernatremia, hyperchloremia, or metabolic acidosis.
The infusion of solutions with 0.45% Sodium Chloride Injection, USP may result in
hyponatremia. Close clinical monitoring may be warranted. Hyponatremia can lead to
headache, nausea, seizures, lethargy, coma, cerebral edema and death. The risk for
hyponatremia is increased, for example, in children, elderly, women, postoperatively, in
persons with psychogenic polydipsia, and in patients treated with medications that
increase the risk of hyponatremia (such as certain antiepileptic and psychotropic
medications). The risk for developing hyponatremic encephalopathy is increased, for
example, in pediatric patients (≤16 years of age), women (in particular pre-menopausal
women), in patients with hypoxemia, and in patients with underlying central nervous
system disease. Acute symptomatic hyponatremic encephalopathy is considered a
medical emergency.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Administer Sodium Chloride Injection, USP with particular caution, to patients with or at
risk for hypervolemia or with conditions that may cause sodium retention, fluid overload
and edema; such as patients with primary hyperaldosteronism, or secondary
hyperaldosteronism [e.g., associated with hypertension, congestive heart failure, liver
disease (including cirrhosis), renal disease (including renal artery stenosis,
nephrosclerosis) or pre-eclampsia]. Certain medications may increase risk of sodium and
fluid retention, see Drug Interactions.
Administer Sodium Chloride Injection, USP with particular caution, to patients with
severe renal impairment. In such patients, administration of Sodium Chloride Injection,
USP may result in sodium retention.
PRECAUTIONS
General
Do not connect flexible plastic containers in series in order to avoid air embolism due to
possible residual air contained in the primary container. Such use could result in air
embolism due to residual air being drawn from the primary container before
administration of the fluid from the secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
Do not mix or administer 0.45% Sodium Chloride Injection, USP through the same
administration set with whole blood or cellular blood components.
Rapid correction of hypo- and hypernatremia is potentially dangerous (risk of serious
neurologic complications). Dosage, rate, and duration of administration should be
determined by a physician experienced in intravenous fluid therapy.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to
patients treated with drugs that may increase the risk of sodium and fluid retention, such
as corticosteroids.
Caution is advised in patients treated with lithium. Renal sodium and lithium clearance
may be decreased in the presence of hyponatremia. Administration of 0.45% Sodium
Chloride Injection, USP may result in increased lithium levels.
Renal sodium and lithium clearance may be increased during administration of 0.9%
Sodium Chloride Injection, USP. Administration of 0.9% Sodium Chloride Injection,
USP, may result in decreased lithium levels.
Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies with Sodium Chloride Injection, USP
in pregnant women and animal reproduction studies have not been conducted with this
drug. Therefore, it is not known whether Sodium Chloride Injection, USP can cause fetal
harm when administered to a pregnant woman. Sodium Chloride Injection, USP should
be given to a during pregnancy only if the potential benefit justifies the potential risk to
the fetus.
Nursing Mothers
It is not known whether this drug is present in human milk. Because many drugs are
present in human milk, caution should be exercised when Sodium Chloride Injection,
USP is administered to a nursing woman.
Pediatric Use
The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical
practice. (See DOSAGE AND ADMINSTRATION).
Plasma electrolyte concentrations should be closely monitored in the pediatric population
as this population may have impaired ability to regulate fluids and electrolytes.
The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with
the non-osmotic secretion of ADH may result in hyponatremia in patients with acute
volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma,
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is
considered a medical emergency.
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
Post-Marketing Adverse Reactions
The following adverse reactions have been identified during postapproval use of Sodium
Chloride Injection, USP. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
The following adverse reactions have been reported in the post-marketing experience
during use of 0.9% Sodium Chloride Injection, USP and include the following:
hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills,
urticaria, rash, and pruritus.
Also reported are infusion site reactions, such as infusion site erythema, injection site
streaking, burning sensation, and infusion site urticaria.
The following adverse reactions have not been reported with 0.9% Sodium Chloride
Injection, USP but may occur: hypernatremia, hyperchloremic metabolic acidosis, and
hyponatremia, which may be symptomatic.
Hyponatremia has been reported for 0.45% Sodium Chloride Injection, USP (see
Pediatric Use section).
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The following adverse reactions have not been reported with 0.45% Sodium Chloride
Injection, USP but may occur: hyperchloremic metabolic acidosis,
hypersensitivity/infusion reactions (including hypotension, pyrexia, tremor, chills,
urticaria, rash, and pruritus), and infusion site reactions (such as infusion site erythema,
injection site streaking, burning sensation, infusion site urticaria).
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures and save the remainder of the fluid for
examination if deemed necessary.
OVERDOSAGE
Excessive administration of 0.45% Sodium Chloride Injection, USP may lead to hypo-
and hypernatremia, while excessive administration of 0.9% Sodium Chloride Injection,
USP may lead to hypernatremia. Both hypo- and hypernatremia can lead to CNS
manifestations, including seizures, coma, cerebral edema and death.
Excessive administration of Sodium Chloride Injection, USP may lead to sodium
overload (which can lead to central and/or peripheral edema).
When assessing an overdose, any additives in the solution must also be considered. The
effects of an overdose may require immediate medical attention and treatment.
DOSAGE AND ADMINISTRATION
All injections in VIAFLEX plastic containers are intended for intravenous administration
using sterile and nonpyrogenic equipment.
As directed by a physician. Dosage, rate, and duration of administration are to be
individualized and depend upon the indication for use, the patient’s age, weight, clinical
condition, concomitant treatment, and on the patient’s clinical and laboratory response to
treatment.
When other electrolytes or medicines are added to this solution, the dosage and the
infusion rate will also be dictated by the dose regimen of the additions.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Use of a
final filter is recommended during administration of all parenteral solutions, where
possible.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not administer unless the solution is clear and seal is intact.
Additives may be incompatible with Sodium Chloride Injection, USP. As with all
parenteral solutions, compatibility of the additives with the solution must be assessed
before addition. Before adding a substance or medication, verify that it is soluble and/or
stable in water and that the pH range of Sodium Chloride Injection, USP is appropriate.
After addition, check for unexpected color changes and/or the appearance of precipitates,
insoluble complexes or crystals.
The instructions for use of the medication to be added and other relevant literature must
be consulted. Additives known or determined to be incompatible must not be used. When
introducing additives to Sodium Chloride Injection, USP, aseptic technique must be used.
Mix the solution thoroughly when additives have been introduced. Do not store solutions
containing additives.
After opening the container, the contents should be used immediately and should not be
stored for a subsequent infusion. Do not reconnect any partially used containers. Discard
any unused portion.
HOW SUPPLIED
The available sizes of each injection in VIAFLEX plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
2B1313
500
0338-0043-03
0.45% Sodium Chloride
Injection, USP
2B1314
1000
0338-0043-04
2B1356
250
0338-1452-02
2B1300
25 Quad Pack
0338-0049-10
0.9% Sodium Chloride
Injection, USP
50
2B1306
Single pack
0338-0049-41
2B1301
Quad pack
0338-0049-11
2B1308
Multi pack
0338-0049-31
100
2B1307
Single pack
0338-0049-48
2B1302
Quad pack
0338-0049-18
2B1309
Multi pack
0338-0049-38
2B1321
150
0338-0049-01
2B1322
250
0338-0049-02
2B1323
500
0338-0049-03
2B1324
1000
0338-0049-04
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C/77°F); brief exposure
up to 40°C/104°F does not adversely affect the product.
DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER
For Information on Risk of Air Embolism – see PRECAUTIONS.
To Open
Tear overwrap down side at slit and remove solution container. Visually inspect the
container. If the outlet port protector is damaged, detached, or not present, discard
container as solution path sterility may be impaired. Some opacity of the plastic due to
moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check
for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as
sterility may be impaired. If supplemental medication is desired, follow directions below.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and
inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and
inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
Distributed in Canada by
Baxter Corporation
Mississauga, ON L5N 0C2
07-19-71-904
Rev. December 2014
Baxter, PL 146, and Viaflex are trademarks of Baxter International Inc.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3% AND 5% SODIUM CHLORIDE INJECTION, USP
IN VIAFLEX PLASTIC CONTAINER
DESCRIPTION
3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic
solution for fluid and electrolyte replenishment in single dose containers for intravenous
administration. The pH may have been adjusted with hydrochloric acid. It contains no
antimicrobial agents. Composition, ionic concentration, osmolarity, and pH are shown in
Table 1.
Table 1
Composition
(g/L)
Ionic Concentration
(mEq/L)
*Osmolarity
(mOsmol/L)
(calc)
pH
size
(mL)
Sodium
Chloride
USP (NaCl)
Sodium
Chloride
3% Sodium
Chloride
Injection,
USP
500
30
513
513
1027
5.0
(4.5 to 7.0)
5% Sodium
Chloride
Injection,
USP
500
50
856
856
1711
5.0
(4.5 to 7.0)
*Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L.
The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). The amount of water that can permeate from inside the
container into the overwrap is insufficient to affect the solution significantly. Solutions in
contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to
5 parts per million. However, the safety of the plastic has been confirmed in tests in
animals according to USP biological tests for plastic containers as well as by tissue
culture toxicity studies.
CLINICAL PHARMACOLOGY
3% and 5% Sodium Chloride Injection, USP has value as a source of water and
electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and
electrolytes.
CONTRAINDICATIONS
None known.
WARNINGS
Hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills,
utricaria, rash, and pruritus may occur with 3% and 5% Sodium Chloride Injection, USP.
Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction
develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic
countermeasures must be instituted as clinically indicated.
Depending on the volume and rate of infusion, the intravenous administration of 3% and
5% Sodium Chloride Injection, USP can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration/hypervolemia, congested
states, pulmonary edema, or acid-base imbalance. The risk of dilutive states is inversely
proportional to the electrolyte concentration of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to
the electrolyte concentrations of the injection.
Monitor changes in fluid balance, electrolyte concentrations, and acid base balance
during prolonged parenteral therapy or whenever the condition of the patient or the rate
of administration warrants such evaluation.
Administer 3% and 5% Sodium Chloride Injection, USP with particular caution to
patients with or at risk for hypernatremia, hypercholermia, hypervolemia or with
conditions that may cause sodium retention, fluid overload and edema; such as patients
with primary hyperaldosteronism, or secondary hyperaldosteronism (for example,
associated with hypertension, congestive heart failure, liver disease (including cirrhosis),
renal disease (including renal artery stenosis, nephrosclerosis) or pre-eclampsia). Certain
medications may increase risk of sodium and fluid retention, see DRUG
INTERACTIONS.
Administer 3% and 5% Sodium Chloride Injection, USP with particular caution to
patients with severe renal impairment. In such patients administration of Sodium
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Chloride Injection, USP may result in sodium retention.
PRECAUTIONS
General
Do not connect flexible plastic containers in series in order to avoid air embolism due to
possible residual air contained in the primary container. Such use could result in air
embolism due to residual air being drawn from the primary container before
administration of the fluid from the secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
3% and 5% Sodium Chloride Injection, USP is hypertonic with an osmolarity of 1027
mOsmol/L and 1711 mOsmol/L, respectively. Administration of hypertonic solutions
may cause venous damage and thus should be administered through a large vein, for
rapid dilution.
Do not mix or administer 3% and 5% Sodium Chloride Injection, USP solutions through
the same administration set with whole blood or cellular blood components.
Rapid correction of hypo- and hypernatremia is potentially dangerous (risk of serious
neurologic complications). Dosage, rate, and duration of administration should be
determined by a physician experienced in intravenous fluid therapy.
Drug Interactions
Caution must be exercised in the administration of 3% and 5% Sodium Chloride
Injection, USP to patients treated with drugs that may increase the risk of sodium and
fluid retention, such as corticosteroids.
Caution is advised in patients treated with lithium. Renal sodium and lithium clearance
may be increased during the administration of 3% and 5% Sodium Chloride Injection,
USP. Administration of 3% and 5% Sodium Chloride Injection, USP may, therefore,
result in decreased lithium levels.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies with 3% and 5% Sodium Chloride
Injection, USP in pregnant women and animal reproduction studies have not been
conducted with this drug. Therefore, it is not known whether 3% and 5% Sodium
Chloride Injection, USP can cause fetal harm when administered to a pregnant woman.
3% and 5% Sodium Chloride Injection, USP should be given during pregnancy only if
the potential benefit justifies the potential risks to the fetus.
Nursing Mothers
It is not known whether this drug is excreted present in human milk. Because many drugs
are excreted present in human milk, caution should be exercised when 3% and 5%
Sodium Chloride Injection, USP is administered to a nursing woman.
Pediatric Use
The use of 3% and 5% Sodium Chloride Injection, USP in pediatric patients is based on
clinical practice. (See DOSAGE AND ADMINISTRATION)
Plasma electrolyte concentrations should be closely monitored in the pediatric population
as this population may have impaired ability to regulate fluids and electrolytes.
Geriatric Use
Clinical studies of 3% and 5% Sodium Chloride Injection, USP, did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Post-Marketing Adverse Reactions
The following adverse reactions have not been reported with 3% and 5% Sodium
Chloride Injection, USP but may occur:
• hyperchloremic metabolic acidosis,
• hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills,
urticaria, rash, and pruritus,
• Infusion site reactions, such as thrombosis, phlebitis, irritation, infusion site
erythema, injection site streaking, burning sensation, infusion site urticaria.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures, and save the remainder of the fluid for
examination if deemed necessary.
OVERDOSAGE
Excessive administration of 3% and 5% Sodium Chloride Injection, USP may lead to
hypernatremia (which can lead to CNS manifestations, including seizures, coma, cerebral
edema and death) and sodium overload (which can lead to central and/or peripheral
edema).
When assessing an overdose, any additives in the solution must also be considered. The
effects of an overdose may require immediate medical attention and treatment.
DOSAGE AND ADMINISTRATION
As directed by a physician. Dosage, rate, and duration of administration are to be
individualized and depend upon the indication for use, the patient’s age, weight, clinical
condition, concomitant treatment, and on the patient’s clinical and laboratory response to
treatment.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Use of a
final filter is recommended during administration of all parenteral solutions, where
possible.
Do not administer unless solution is clear and seal is intact.
All injections in VIAFLEX plastic containers are intended for intravenous administration
using sterile and nonpyrogenic equipment.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Additives may be incompatible. Complete information is not available. Those additives
known to be incompatible should not be used. Consult with pharmacist, if available. If, in
the informed judgment of the physician, it is deemed advisable to introduce additives, use
aseptic technique. Mix thoroughly when additives have been introduced. Do not store
solutions containing additives.
After opening the container, the contents should be used immediately and should not be
stored for a subsequent infusion. Do not reconnect any partially used containers. Discard
any unused portion.
HOW SUPPLIED
3% and 5% Sodium Chloride Injection, USP in VIAFLEX plastic container is available
as follows:
Code
Size (mL)
NDC
Product Name
2B1353
500
0338-0054-03
3% Sodium Chloride Injection, USP
2B1373
500
0338-0056-03
5% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C/77°F); brief exposure
up to 40°C /104°F does not adversely affect the product.
DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER
For Information on Risk of Air Embolism – see PRECAUTIONS.
To Open
Tear overwrap down side at slit and remove solution container. Visually inspect the
container. If the outlet port protector is damaged, detached, or not present, discard
container as solution path sterility may be impaired. Some opacity of the plastic due to
moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check
for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as
sterility may be impaired. If supplemental medication is desired, follow directions below.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Warning: Additives may be incompatible - see DOSAGE AND ADMINISTRATION.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
07-19-72-006
Rev. December 2014
Baxter, PL 146 and Viaflex are trademarks of Baxter International Inc.
Reference ID: 3676997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:28.767090
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019022s026lbl.pdf', 'application_number': 18016, 'submission_type': 'SUPPL ', 'submission_number': 62}
|
11,109
|
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 4
Baxter
OSMITROL Injection (Mannitol Injection, USP)
in AVIVA Plastic Container
For Therapeutic Use Only
Description
Osmitrol Injection (Mannitol Injection, USP) is a sterile, nonpyrogenic solution of Mannitol, USP in a
single dose container for intravenous administration. It contains no antimicrobial agents. Mannitol**
is a six carbon sugar alcohol prepared commercially by the reduction of dextrose. Although virtually
inert metabolically in humans, it occurs naturally in fruits and vegetables. Mannitol is an obligatory
osmotic diuretic. The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.
Composition, osmolarity, and pH are shown in Table 1.
Composition
Table 1
Size
(mL)
**Mannitol,
USP (g/L)
*Osmolarity
(mOsmol/L)
(calc)
pH
5%
OSMITROL
Injection (5%
Mannitol
Injection, USP)
1000
50
274
5.5
(4.5 TO 7.0)
500
10%
OSMITROL
Injection (10%
Mannitol
Injection, USP)
1000
100
549
5.5
(4.5 TO 7.0)
15%
OSMITROL
Injection (15%
Mannitol
Injection, USP)
500
150
823
5.5
(4.5 TO 7.0)
250
20%
OSMITROL
Injection (20%
Mannitol
Injection, USP)
500
200
1098
5.5
(4.5 TO 7.0)
*Normal physiologic osmolarity range is approximately 280 to 310 m0smol/L.
Administration of substantially hypertonic solutions (≥ 600 m0smol/L) may cause vein damage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 5
Mannitol
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for the attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Osmitrol Injection (Mannitol Injection, USP) is one of the nonelectrolyte, obligatory, osmotic
diuretics. It is freely filterable at the renal glomerulus, only poorly reabsorbed by the renal tubule, not
secreted by the tubule, and is pharmacologically inert.
Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small
molecular size being largely confined to the extracellular space. Only relatively small amounts of the
dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney
over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a
100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even
at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted
by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 6
and chloride by elevating the osmolarity of the glomerular filtrate.
This increase in extracellular osmolarity effected by the intravenous administration of mannitol will
induce the movement of intracellular water to the extracellular and vascular spaces. This action
underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated
intraocular pressure.
Indications and Usage
Osmitrol Injection (Mannitol Injection, USP) is indicated for:
The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal
failure before irreversible renal failure becomes established;
The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass;
The reduction of elevated intraocular pressure when the pressure cannot be lowered by other means,
and promoting the urinary excretion of toxic substances.
Contraindications
Osmitrol Injection (Mannitol Injection, USP) is contraindicated in patients with:
Well established anuria due to severe renal disease, severe pulmonary congestion or frank pulmonary
edema, active intracranial bleeding except during craniotomy, severe dehydration,Progressive renal
damage or dysfunction after institution of mannitol therapy, including increasing oliguria and
azotemia, and progressive heart failure or pulmonary congestion after institution of mannitol therapy.
Warnings
In patients with severe impairment of renal function, a test dose should be utilized (see Dosage and
Administration). A second test dose may be tried if there is an inadequate response, but no more than
two test doses should be attempted.
The obligatory diuretic response following rapid infusion of 15% or 20% mannitol injection may
further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to
serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol
administration.
If urine output continues to decline during mannitol infusion, the patient’s clinical status should be
closely reviewed and mannitol infusion suspended if necessary. Accumulation of mannitol may result
in overexpansion of the extracellular fluid which may intensify existing or latent congestive heart
failure.
Excessive loss of water and electrolytes may lead to serious imbalances. With continued
administration of mannitol, loss of water in excess of electrolytes can cause hypernatremia. Electrolyte
measurements, including sodium and potassium, are therefore, of vital importance in monitoring the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 7
infusion of mannitol.
Osmotic nephrosis, a reversible vacuolization of the tubules of unknown clinical significance, may
proceed to severe irreversible nephrosis, so that the renal function must be closely monitored during
mannitol infusion.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
The cardiovascular status of the patient should be carefully evaluated before rapidly administrating
mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart
failure.
Shift of sodium free intracellular fluid into the extracellular compartment following mannitol infusion
may lower serum sodium concentration and aggravate preexisting hyponatremia.
By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or
hypovolemia.
Electrolyte free mannitol should not be given conjointly with blood. If it is essential that blood be
given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol
solution to avoid pseudoagglutination.
When exposed to low temperatures, solutions of mannitol may crystallize. Concentrations greater than
15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals
are visible, redissolve by warming the solution up to 70°C, with agitation. Allow the solution to cool
to room temperature before reinspection for crystals. Administer intravenously using sterile, filter-
type administration set.
Laboratory Tests
Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 8
The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or
hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding
excessive fluid and electrolyte shifts. The routine features of physical examination and clinical
chemistries suffice in achieving an adequate degree of appropriate patient monitoring.
Drug Interaction
Studies have not been conducted to evaluate drug/drug or drug/food interactions with Osmitrol
Injection (Mannitol Injection, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Osmitrol Injection (Mannitol Injection, USP) have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with mannitol. It is also
not known whether mannitol can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. Mannitol should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Osmitrol Injection (Mannitol Injection,
USP) on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when mannitol is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in children below the age of 12 have not been established.
Usage in Children
Dosage requirements for patients 12 years of age and under have not been established.
Geriatric Use
Clinical studies of Osmitrol Injection (Mannitol Injection, USP) did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 9
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Extensive use of mannitol over the last several decades has produced recorded adverse events, in a
variety of clinical settings, that are isolated or idiosyncratic in nature. None of these adverse reactions
have occurred with any great frequency nor with any security in attributing them to mannitol.
The inability to clearly exclude the drug related nature of such events in these isolated reports prompts
the necessity to list the reactions that have been observed in patients during or following mannitol
infusion. In this fashion, patients have exhibited nausea, vomiting, rhinitis, local pain, skin necrosis
and thrombophlebitis at the site of infection, chills, dizziness, urticaria, hypotension, hypertension,
tachycardia, fever and angina-like chest pains.
Of far greater clinical significance is a variety of events that are related to inappropriate recognition
and monitoring of fluid shifts. These are not intrinsic adverse reactions to the drug but the
consequence of manipulating osmolarity by any agency in a therapeutically inappropriate manner.
Failure to recognize severe impairment of renal function with the high likelihood of nondiuretic
response can lead to aggravated dehydration of tissues and increased vascular fluid load. Induced
diuresis in the presence of preexisting hemoconcentration and preexisting deficiency of water and
electrolytes can lead to serious imbalances. Expansion of the extracellular space can aggravate cardiac
decompensation or induce it in the presence of latent heart failure. Pulmonary congestion or edema
can be seriously aggravated with the expansion of the extracellular and therefore intravascular fluid
load. Hemodilution and dilution of the extracellular fluid space by osmotic shift of water can induce or
aggravate preexisting hyponatremia.
If unrecognized, such fluid and/or electrolyte shift can produce the reported adverse reactions of
pulmonary congestion, acidosis, electrolyte loss, dryness of mouth, thirst, edema, headache, blurred
vision, convulsions and congestive cardiac failure.
These are not truly adverse reactions to the drug and can be appropriately prevented by evaluation of
degree of renal failure with a test dose response to mannitol when indicated; evaluation of
hypervolemia and hypovolemia; sodium and potassium levels; hemodilution or hemoconcentration;
and evaluation of renal, cardiac and pulmonary function at the onset of therapy.
Dosage and Administration
Osmitrol Injection (Mannitol Injection, USP) should be administered only by intravenous infusion.
The total dosage, concentration, and rate of administration should be governed by the nature and
severity of the condition being treated, fluid requirement, and urinary output. The usual adult dosage
ranges from 20 to 100 g in a 24 hour period, but in most instances an adequate response will be
achieved at a dosage of approximately 50 to 100 g in a 24 hour period. The rate of administration is
usually adjusted to maintain a urine flow of at least 30 to 50 mL/hour. This outline of administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 10
and dosage is only a general guide to therapy.
Parenteral dug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of a final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
Test Dose: A test dose of mannitol should be given prior to instituting Osmitrol Injection (Mannitol
Injection, USP) therapy for patients with marked oliguria, or those believed to have inadequate renal
function. Such a test dose may be approximately 0.2 g/kg body weight (about 75 mL of a 20%
solution or 100 mL of a 15% solution) infused in a period of three to five minutes to produce a urine
flow of at least 30 to 50 mL/hour. If urine flow does not increase, a second test dose may be given; if
there is an inadequate response, the patient should be reevaluated.
Prevention of Acute Renal Failure (Oliguria): When used during cardiovascular and other types of
surgery, 50 to 100 g of mannitol as a 5, 10, or 15% solution may be given. The concentration will
depend upon the fluid requirements of the patient.
Treatment of Oliguria: The usual dose for treatment of oliguria is 100 g administered as a 15 or 20%
solution.
Reduction of Intraocular Pressure: A dose of 1.5 to 2.0 g/kg as a 20% solution (7.5 to 10 mL/kg) or as
a 15% solution (10 to 13 mL/kg) may be given over a period as short as 30 minutes in order to obtain a
prompt and maximal effect. When used preoperatively the dose should be given one to one and one-
half hours before surgery to achieve maximal reduction of intraocular pressure before operation.
Reduction of Intracranial Pressure: Usually a maximum reduction in intracranial pressure in adults can
be achieved with a dose of 0.25 g/kg given not more frequently than every six to eight hours. An
osmotic gradient between the blood and cerebrospinal fluid of approximately 10 m0smols will yield a
satisfactory reduction in intracranial pressure.
Adjunctive Therapy for Intoxications: As an agent to promote diuresis in intoxications, 5%, 10%, 15%
or 20% mannitol is indicated. The concentration will depend upon the fluid requirement and urinary
output of the patient.
Measurement of glomerular filtration rate by creatinine clearance may be useful for determination of
dosage.
All injections in AVIVA containers are intended for intravenous administration using sterile
equipment.
The use of supplemental additive medication is not recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 11
How Supplied
Osmitrol Injection (Mannitol Injection, USP) in AVIVA plastic containers is available as follows:
Code
Size (mL)
NDC
Product Name
6E5604
1000
0338-6300-04
5% Osmitrol Injection
(5% Mannitol Injection, USP)
6E5613
6E5614
500
1000
0338-6301-03
0338-6301-04
10% Osmitrol Injection
(10% Mannitol Injection, USP)
6E5623
500
0338-6302-03
15% Osmitrol Injection
(15% Mannitol Injection, USP)
6E5632
6E5633
250
500
0338-6303-02
0338-6303-03
20% Osmitrol Injection
(20% Osmitrol Injection)
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 12
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, OSMITROL, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 13
Baxter
Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below.
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an
osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an
osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 14
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis
procedures.
Contraindications
None known.
Warnings
Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
In patients with diminished renal function, administration of Sodium Chloride Injection, USP may
result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 15
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride
Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in
the pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in the responses between elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 16
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
The available sizes of each injection in AVIVA plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
6E1313
500
0338-6333-03
0.45% Sodium Chloride Injection,
USP
6E1314
1000
0338-6333-04
6E1356
250
0338-6333-02
6E1322
250
0338-6304-02
0.9% Sodium Chloride Injection,
USP
6E1323
500
0338-6304-03
6E1324
1000
0338-6304-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C/77°F); brief exposure up to
40°C(104°F) does not adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 17
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
For Product Information
1-800-833-0303
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 18
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 19
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 20
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 21
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 22
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 23
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 24
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 25
Baxter
Lactated Ringer’s and 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
Each 100 mL contains 5 g Dextrose Hydrous, USP*; 600 mg Sodium Chloride, USP (NaCl); 310 mg
Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride,
USP (CaCl2•2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of
water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq
potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L
(calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions may cause vein damage. The caloric content is 180 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 26
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate
ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of
hydrogen cations.
Indications and Usage
Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and
calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care. If at all, in patients
with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists
edema with sodium retention.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients
with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care in patients with
metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in
those conditions in which there is an increased level or an impaired utilization of these ions, such as
severe hepatic insufficiency.
Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with
blood through the same administration set because of the likelihood of coagulation.
The intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid
and/or solute overloading resulting is dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 27
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Lactated Ringer’s and 5% Dextrose
Injection, USP may result in sodium or potassium retention.
Lactated Ringer’s and 5% Dextrose Injection, USP is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt
or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Lactated Ringer's and 5% Dextrose Injection, USP
to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Lactated Ringer's and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 28
Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s
and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Lactated Ringer's and 5% Dextrose
Injection, USP on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Lactated Ringer’s and 5% Dextrose Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients
have not been established by adequate and well controlled trials, however, the use of lactated ringer’s
and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum amorality and possible hemorrhage.
Geriatric Use
Clinical studies of Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in the responses between
elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Allergic reactions or anaphylactic symptoms such as localized or generalized urinary and purities; per
orbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 29
reported during administration of Lactated Ringer’s and 5% Dextrose Injection, USP. The reporting
frequency of these signs and symptoms is higher in women during pregnancy.
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasations, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown
below:
Code
Size
NDC
6E2073
500 mL
NDC 0338-6306-03
6E2074
1000 mL
NDC 0338-6306-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 30
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 31
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 32
Baxter
Lactated Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
Composition (g/L)
Ionic Concentration (mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP, (NaCl)
Sodium Lactate, (C3H5NaO3)
Potassium Chloride, USP, (KCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
Lactate
Caloric Content
(kcal/L)
250
500
Lactated
Ringer’s
Injection, USP
1000
6
3.1
0.3
0.2
273
6.5
(6.0 to 7.5)
130
4
2.7
109
28
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 33
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are
metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen
cations.
Indications and Usage
Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing
agent.
Contraindications
None known
Warnings
Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Lactated Ringer’s Injection, USP should be used with great care in patients with metabolic or
respiratory alkalosis. The administration of lactate ions should be done with great care in those
conditions in which there is an increased level or an impaired utilization of these ions, such as severe
hepatic insufficiency.
Lactated Ringer’s Injection, USP should not be administered simultaneously with blood through the
same administration set because of the likelihood of coagulation.
The intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute
overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states,
or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte
concentration of the injections. The risk of solute overload causing congested states with peripheral
and pulmonary edema is directly proportional to the electrolyte concentrations of the injections.
In patients with diminished renal function, administration of Lactated Ringer’s Injection, USP may
result in sodium or potassium retention. Lactated Ringer’s injection, USP is not for use in the
treatment of lactic acidosis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 34
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Lactated Ringer’s Injections, USP must be used with caution. Excess administration may result in
metabolic alkalosis.
Laboratory Test
CLINICAL EVALUATION AND PERIODIC LABORATORY DETERMINATIONS ARE NECESSARY TO MONITOR
CHANGES IN FLUID BALANCE, ELECTROLYTE CONCENTRATIONS, AND ACID BASE BALANCE DURING
PROLONGED PARENTERAL THERAPY OR WHENEVER THE CONDITION OF THE PATIENT WARRANTS SUCH
EVALUATION.
Drug Interactions
Caution must be exercised in the administration of Lactated Ringer's Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Lactated Ringer's Injection, USP.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
STUDIES WITH LACTATED RINGER'S INJECTION, USP HAVE NOT BEEN PERFORMED TO EVALUATE
CARCINOGENIC POTENTIAL, MUTAGENIC POTENTIAL, OR EFFECTS ON FERTILITY.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s
Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Lactated Ringer's Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 35
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Lactated Ringer's Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of electrolyte solutions in the
pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function and concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Allergic reactions or anaphylactoid symptoms such as localized or generalized urticaria and pruritis;
periorbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have
been reported during administration of Lactated Ringer’s Injection, USP. The reporting frequency of
these signs and symptoms is higher in women during pregnancy.
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
infection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 36
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2322
250
0338-6307-02
6E2323
500
0338-6307-03
6E2324
1000
0338-6307-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40° C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 37
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 38
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 39
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 40
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 41
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 42
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 43
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 44
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 45
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 46
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 47
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 48
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 49
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 50
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 51
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 52
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 53
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 54
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 55
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 56
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 57
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 58
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 59
Baxter
Sodium Lactate Injection, USP (M/6 Sodium Lactate)
in AVIVA Plastic Container
Description
Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition,
osmolarity, pH, ionic concentration and caloric content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
Size
(mL)
Sodium Lactate
(C3H5NaO3)
*Osmolarity
(mOsmol/L)
(calc)
pH
Sodium
Lactate
Caloric Content
(kcal/L)
500
Sodium
Lactate
Injection, USP
(M/6 Sodium
Lactate)
1000
18.7
334
6.5
(6.0 to 7.3)
167
167
54
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 60
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable
of inducing diuresis depending on the clinical condition of the patient.
Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized
ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an
alkalinizing agent.
Contraindications
None known
Warnings
Sodium Lactate Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Sodium Lactate Injection, USP should be used with great care in patients with metabolic or respiratory
alkalosis. The administration of lactate ions should be done with great care in those conditions in
which there is an increased level or an impaired utilization of these ions, such as severe hepatic
insufficiency.
The intravenous administration of these injections can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
Excessive administration of Sodium Lactate Injection, USP may result in significant hypokalemia.
In patients with diminished renal function, administration of Sodium Lactate Injection, USP may result
in sodium retention.
Sodium Lactate Injection, USP is not for use in the treatment of lactic acidosis.
Precautions
General
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 61
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Sodium Lactate Injection, USP (M/6 Sodium
Lactate) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Lactate Injection, USP (M/6 Sodium Lactate).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Lactate Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Lactate
Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP (M/6
Sodium Lactate) on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Sodium Lactate Injection, USP is administered to a
nursing mother.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 62
Pediatric Use
Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of sodium lactate solutions in the
pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Lactate Injection, USP did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of a final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 63
How Supplied
Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA plastic container is available as
follows:
Code
Size (mL)
NDC
6E1803
500
0338-6311-03
6E1804
1000
0338-6311-04
EXPOSURE OF PHARMACEUTICAL PRODUCTS TO HEAT SHOULD BE MINIMIZED. AVOID EXCESSIVE
HEAT. IT IS RECOMMENDED THE PRODUCT BE STORED AT ROOM TEMPERATURE (25°C); BRIEF
EXPOSURE UP TO 40°C DOES NOT ADVERSELY AFFECT THE PRODUCT.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 64
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 65
Baxter
Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in
single dose containers for intravenous administration. It contains no antimicrobial agents. The pH
may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration
are shown in Table 1.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP (NaCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Potassium Chloride, USP (KCl)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
500
Ringer’s
Injection,
USP
1000
8.6
0.33
0.3
309
5.5
(5.0 to 7.5)
147.5
4
4.5
156
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 66
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing
diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart
failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe
renal failure, and in conditions in which potassium retention is present.
Ringer’s Injection, USP should not be administered simultaneously with blood through the same
administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading
resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 67
edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the
injection. The risk of solute overload causing congested states with peripheral and pulmonary edema
is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s Injection, USP may result in
sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving
corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer’s Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential,
mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection,
USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a
pregnant woman only if clearly needed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 68
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and
delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by
adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 69
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2303
500
NDC 0338-6312-03
6E2304
1000
NDC 0338-6312-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 70
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 71
Baxter
Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in
single dose containers for intravenous administration. It contains no antimicrobial agents. The pH
may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration
are shown in Table 1.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP (NaCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Potassium Chloride, USP (KCl)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
500
Ringer’s
Injection,
USP
1000
8.6
0.33
0.3
309
5.5
(5.0 to 7.5)
147.5
4
4.5
156
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 72
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing
diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart
failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe
renal failure, and in conditions in which potassium retention is present.
Ringer’s Injection, USP should not be administered simultaneously with blood through the same
administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading
resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary
edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the
injection. The risk of solute overload causing congested states with peripheral and pulmonary edema
is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s Injection, USP may result in
sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 73
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving
corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer’s Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential,
mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection,
USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and
delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by
adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 74
Geriatric Use
Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2303
500
NDC 0338-6312-03
6E2304
1000
NDC 0338-6312-04
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 75
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 76
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 77
Baxter
Ringer’s and 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Ringer’s and 5% Dextrose Injection, USP is sterile, nonpyrogenic solution for fluid and electrolyte
replenishment and caloric supply in a single dose container for intravenous administration. Each 100
mL contains 5 g Dextrose Hydrous, USP*; 860 mg of Sodium Chloride, USP (NaCl); 33 mg of
Calcium Chloride, USP (CaCl2•2H2O); and 30 mg of Potassium Chloride, USP (KCl). It contains no
antimicrobial agents. The pH is 4.0 (3.5 to 6.5).
c
*
D-Glucopyranose monohydrate
Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water,
electrolytes, and calories. One liter has an ionic concentration of 147.5 mEq sodium, 4.5 mEq calcium,
4 mEq potassium, and 156 mEq chloride. The osmolarity is 561 mOsmol/L (calc). Normal
physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions may cause vein damage. The caloric content is 170 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 78
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It
is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood
through the same administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or
solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested
states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte
concentrations of the injection. The risk of solute overload causing congested states with peripheral
and pulmonary edema is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s and 5% Dextrose Injection, USP
may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 79
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Ringer's and 5% Dextrose Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer's and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer's and 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer's and 5%
Dextrose Injection, USP. It is also not known whether Ringer's and 5% Dextrose Injection, USP can
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer's
and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer's and 5% Dextrose Injection, USP on
labor and delivery. Caution should be exercised when administering this drug during labor and
delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Ringer's and 5% Dextrose Injection, USP is
administered to a nursing woman.
Pediatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 80
Safety and effectiveness of Ringer's and 5% Dextrose Injection, USP in pediatric patients have not
been established by adequate and well controlled trials, however, the use of ringer's and dextrose
solutions in the pediatric population is referenced in the medical literature. The warnings, precautions
and adverse reactions identified in the label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Ringer's and 5% Dextrose Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 81
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Ringer's and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2064
1000
NDC 0338-6313-04
6E2063
500
NDC 0338-6313-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C): brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 82
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter Healthcare International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 83
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 84
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 85
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 86
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 87
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 88
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 89
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 90
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 91
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 92
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 93
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 94
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 95
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 96
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 97
Baxter
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1,
USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile,
nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL
contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl);
and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH
is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0).
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq
acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions may cause vein damage. The caloric content is 21 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 98
Clinical Pharmacology
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic
alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water,
which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source
of water and electrolytes or as an alkalinizing agent.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with
blood or blood components. It may be administered prior to or following the infusion of blood through
the same administration set (i.e., as a priming solution), added to or infused concurrently with blood
components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148
Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood
components.
Contraindications
None known
Warnings
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical
states in which there exists edema with sodium retention.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which
potassium retention is present.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care in patients with metabolic or respiratory alkalosis. The administration of acetate or
gluconate ions should be done with great care in those conditions in which there is an increased level
or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection,
Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 99
In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-
LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection
(Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly
needed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 100
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE 148 Injection (Multiple Electrolytes
Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) did
not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 101
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2534
1000
NDC 0338-6316-04
6E2533
500
NDC 0338-6316-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 102
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 103
Baxter
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection,
Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile,
nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL
contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl);
and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH
is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0).
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a sousrce of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq
acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic
osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may
cause vein damage. The caloric content is 21 lcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 104
Clinical Pharmacology
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a
source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition
of the patient.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a
metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide
and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a
source of water and electrolytes or as an alkalinizing agent.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with
blood or blood components. It may be administered prior to or following the infusion of blood through
the same administration set (i.e., as a priming solution), added to or infused concurrently with blood
components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A
Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood
components.
Contraindications
None known
Warnings
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in
clinical states in which there exists edema with sodium retention.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which
potassium retention is present.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or
gluconate ions should be done with great care in those conditions in which there is an increased level
or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes
Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional
states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 105
overload causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4
(Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) have
not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal
harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 106
A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE A Injection pH 7.4
(Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised
when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE A Injection pH 7.4 (Multiple
Electrolytes Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type
1, USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP)
did not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elkerly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 107
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2544
1000
NDC 0338-6317-04
6E2543
500
NDC 0338-6317-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 108
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 109
Baxter
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 234 mg Sodium Chloride, USP (NaCl); 128 mg Potassium Acetate, USP (C2H3KO2); and 32 mg
Magnesium Acetate, Tetrahydrate (C4H6MgO4•4H2O). It contains no antimicrobial agents. pH 5.0
(4.0 to 6.5). The pH is adjusted with hydrochloric acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq
chloride, and 16 mEq acetate. The osmolarity is 363 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 170 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 110
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon
dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of acetate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 111
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should not be administered simultaneously with blood through the same administration set
because of the possibility of pseudoagglutination or hemolysis.
The intravenous administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 56 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 56 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 112
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also
not known whether PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE 56 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 113
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 114
6E2573
500
NDC 0338-6318-03
6E2574
1000
NDC 0338-6318-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 115
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 116
Baxter
PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 161 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 138 mg Sodium Lactate
(C3H5NaO3), 119 mg Potassium Chloride, USP (KCl), 94 mg Sodium Chloride, USP (NaCl), 37 mg
Calcium Chloride, USP (CaCl2•2H2O), and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It
contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric
acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 16 mEq potassium, 5 mEq calcium, 3 mEq magnesium,
40 mEq chloride, 12 mEq acetate, and 12 mEq lactate. The osmolarity is 377 mOsmol/L (calc).
Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is
180 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 117
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to
carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 118
administration of lactate or acetate ions should be done with great care in those conditions in which
there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should not be administered simultaneously with blood through the same administration set
because of the likelihood of coagulation.
The intravenous administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 2, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE M and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) containing sodium or potassium
ions may result in sodium or potassium retention.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 119
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). It is also
not known whether PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE M and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 2, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 120
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 121
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) in AVIVA plastic containers is available as shown below:
Size (mL)
Code
NDC
1000
6E2564
NDC 0338-6319-04
500
6E2563
NDC 0338-6319-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 122
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 123
Baxter
PLASMA-LYTE R INJECTION (Multiple Electrolytes Injection, Type
2, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is a sterile, nonpyrogenic
isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 640
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 496 mg of Sodium Chloride, USP (NaCl);
89.6 mg of Sodium Lactate (C3H5NaO3); 74.6 mg of Potassium Chloride, USP (KCl); 36.8 mg of
Calcium Chloride, USP (CaCl2•2H2O); and 30.5 mg of Magnesium Chloride, USP (MgCl2•6H2O). It
contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to
8.0).
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) administered
intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 10 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 103 mEq
chloride, 47 mEq acetate, and 8 mEq lactate. The osmolarity is 312 mOsmol/L (calc). Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially
hypertonic solutions may cause vein damage. The caloric content is 11 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 124
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) produces a metabolic
alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water,
which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is indicated as a source of
water and electrolytes or as an alkalinizing agent.
Contraindications
None known
Warnings
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states
in which there exists edema with sodium retention.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium
retention is present.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care in patients with metabolic or respiratory alkalosis. The administration of lactate or acetate ions
should be done with great care in those conditions in which there is an increased level or an impaired
utilization of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should not be
administered simultaneously with blood through the same administration set because of the likelihood
of coagulation.
The intravenous administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type
2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE R Injection (Multiple
Electrolytes Injection, Type 2, USP) may result in sodium or potassium retention. PLASMA-LYTE R
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 125
Injection (Multiple Electrolytes Injection, Type 2, USP) is not for use in the treatment of lactic
acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE R Injection (Multiple Electrolytes
Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
R Injection (Multiple Electrolytes Injection, Type 2, USP). It is also not known whether PLASMA-
LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE R Injection
(Multiple Electrolytes Injection, Type 2, USP) should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 126
Studies have not been conducted to evaluate the effects of PLASMA-LYTE R Injection (Multiple
Electrolytes Injection, Type 2, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE R Injection (Multiple Electrolytes
Injection, Type 2, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 127
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2504
1000
NDC 0338-6320-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 128
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium
chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 129
Baxter
PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in
a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg
Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30
mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0
to 6.5). The pH is adjusted with hydrochloric acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq
chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially
hypertonic solutions (>600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 130
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized
ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and
in conditions in which potassium retention is present.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of acetate or gluconate ions should be done with great care in those conditions in which
there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 131
The intravenous administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 148 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 132
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also
not known whether PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and
well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 133
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) in AVIVA plastic containers is available as shown below:
Size (mL)
Code
NDC
1000
6E2584
NDC 0338-6321-04
500
6E2583
NDC 0338-6321-03
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 134
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 135
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 136
Baxter
5% Dextrose and Electrolyte No. 48 Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 260 mg Sodium Lactate (C3H5NaO3), 141 mg Potassium Chloride, USP (KCl), 31 mg
Magnesium Chloride, USP (MgCl2•6H20), 20 mg Monobasic Potassium Phosphate, NF (KH2PO4), and
12 mg Sodium Chloride, USP (NaCl). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 25 mEq sodium, 20 mEq potassium, 3 mEq magnesium, 24 mEq
chloride, 23 mEq lactate and 3 mEq phosphate as HPO4
=. The osmolarity is 348 mOsmol/L (calc).
Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is
180 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 137
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon
dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of lactate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 138
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should not be administered simultaneously with blood through the same administration set
because of the possibility of pseudoagglutination or hemolysis.
The intravenous administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of
solute overload causing congested states with peripheral and pulmonary edema is directly proportional
to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 48
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Do not administer simultaneously with blood.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 139
Drug Interactions
Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 48 Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5%
Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and
Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not
known whether 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 48
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when 5% Dextrose and Electrolyte No. 48 Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of dextrose and electrolytes solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemmorhage.
Geriatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 140
Clinical studies of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in the responses between elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or
drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 141
How Supplied
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2102
250
NDC 0338-6322-02
6E2103
500
NDC 0338-6322-03
6E2104
1000
NDC 0338-6322-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 142
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 143
Baxter
Potassium Chloride in 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
Composition
(g/L)
Ionic
Concentration
(mEq/L)
Table 1
Potassium Chloride in 5%
Dextrose Injection, USP
mEq Potassium
Size (mL)
**Dextrose Hydrous, USP
Potassium Chloride, USP (KCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Potassium
Chloride
Caloric Content (kcal/L)
10 mEq
1000
50
0.75
272
4.5
(3.5 to 6.5)
10
10
170
20 mEq
1000
50
1.5
293
4.5
(3.5 to 6.5)
20
20
170
30 mEq
1000
50
2.24
312
4.5
(3.5 to 6.5)
30
30
170
40 mEq
1000
20 mEq
500
50
3
333
4.5
(3.5 to 6.5)
40
40
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 144
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system. The flexible container is a closed
system, and air is prefilled in the container to facilitate drainage. The container does not require entry
of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwarp is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose Injection, USP is a source of water, electrolytes and calories. It is
capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Potassium Chloride in 5% Dextrose Injection, USP should be used with great care, if at all, in patients
with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The bag label for these injections bears the statement: Do not
administer simultaneously with blood.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 145
The intravenous administration of Potassium Chloride in 5% Dextrose Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose
Injection, USP may result in potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Potassium Chloride in 5% Dextrose Injection, USP should be used with caution in patients with overt
or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Studies have not been conducted to evaluate drug/drug or drug/food interactions with Potassium
Chloride in 5% Dextrose Injection, USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 146
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in 5%
Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Potassium Chloride in 5% Dextrose Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose
Injection, USP on labor and delivery. Caution should be exercised when administering this drug labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose Injection in pediatric patients have not
been established by adequate and well-controlled studies. However, the use of potassium chloride
injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not
feasible is referenced in the medical literature.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indication and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose Injection, USP did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in the responses between
elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 147
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of a final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of
the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Potassium Chloride in 5% Dextrose Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
Product Name
6E1124
1000
0338-6323-04
10 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1134
1000
0338-6324-04
20 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 148
6E1174
1000
0338-6325-04
30 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1264
1000
0338-6326-04
40 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1263
500
0338-6326-03
20 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 149
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 150
Baxter
Potassium Chloride in Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Potassium Chloride in Sodium Chloride Injection, USP is a sterile, nonpyrogenic, solution for fluid
and electrolyte replenishment in a single dose container for intravenous administration. It contains no
antimicrobial agents. Composition, osmolarity, pH and ionic concentration are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium
Chloride, USP
(NaCl)
Potassium
Chloride, USP
(KCl)
*Osmolarity (mOsmol/L)
(Calc.)
pH
Sodium
Potassium
Chloride
20 mEq/L Potassium Chloride in
0.9% Sodium Chloride Injection,
USP
1000
9
1.5
348
5.5
(3.5 to 6.5)
154
20
174
40 mEq/L Potassium Chloride in
0.9% Sodium Chloride Injection,
USP
1000
9
3
388
5.5
(3.5 to 6.5)
154
40
194
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 151
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in Sodium Chloride Injection, USP has value as a source of water and electrolytes.
It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Potassium Chloride in Sodium Chloride Injection, USP is indicated as a source of water and
electrolytes.
Contraindications
None known
Warnings
Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in
patients with congestive heart failure, severe renal insufficiency and in clinical states in which there
exists edema with sodium retention.
Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in
patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is
present.
The intravenous administration of Potassium Chloride in Sodium Chloride Injection, USP can cause
fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Potassium Chloride in Sodium Chloride
Injection, USP may result in sodium or potassium retention.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 152
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in Sodium Chloride Injection,
USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in Sodium Chloride Injection, USP have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in
Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. Potassium Chloride in Sodium Chloride Injection, USP should be given
to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in Sodium Chloride
Injection, USP on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in Sodium Chloride Injection, USP
is administered to a nursing mother.
Pediatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 153
Safety and effectiveness of Potassium Chloride in Sodium Chloride Injection, USP in pediatric patients
have not been established by adequate and well-controlled studies. However, the use of potassium
chloride injection in pediatric patients to treat potassium deficiency states when oral replacement
therapy is not feasible is referenced in the medical literature.
Geriatric Use
Clinical studies of Potassium Chloride in Sodium Chloride Injection, USP did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in the responses between
elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 154
Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container is available as
follows:
Code
Size (mL)
NDC
Product Name
6E1764
1000
0338-6327-04
20 mEq/L
Potassium Chloride
in 0.9% Sodium
Chloride Injection,
USP
6E1984
1000
0338-6328-04
40 mEq/L
Potassium Chloride
in 0.9% Sodium
Chloride Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25º C/77° F); brief exposure up to 40º C
(104º F) does not adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 155
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 156
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 157
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 158
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 159
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 160
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 161
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in the
responses between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Use of a final filter is recommended during administration of all parenteral solutions, where possible.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 162
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 163
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 164
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 165
Baxter
Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below.
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an
osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an
osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 166
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis
procedures.
Contraindications
None known.
Warnings
Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
In patients with diminished renal function, administration of Sodium Chloride Injection, USP may
result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 167
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride
Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in
the pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in the responses between elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 168
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
The available sizes of each injection in AVIVA plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
6E1313
500
0338-6333-03
0.45% Sodium Chloride Injection,
USP
6E1314
1000
0338-6333-04
6E1356
250
0338-6333-02
6E1322
250
0338-6304-02
0.9% Sodium Chloride Injection,
USP
6E1323
500
0338-6304-03
6E1324
1000
0338-6304-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C/77°F); brief exposure up to
40°C(104°F) does not adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 169
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
For Product Information
1-800-833-0303
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 170
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 171
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 172
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 173
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 174
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 175
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in the
responses between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Use of a final filter is recommended during administration of all parenteral solutions, where possible.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 176
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 177
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 178
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 179
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 180
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 181
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 182
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 183
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 184
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in the
responses between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Use of a final filter is recommended during administration of all parenteral solutions, where possible.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 185
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 186
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 187
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 188
Baxter
5% Dextrose and Electrolyte No. 75 Injection
(Multiple Electrolytes and Dextrose Injection, Type 3, USP)
in AVIVA Plastic Container
Description
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 220 mg Sodium Lactate (C3H5Na03), 205 mg Potassium Chloride, USP (KCl), 120 mg Sodium
Chloride, USP (NaCl), and 100 mg Monobasic Potassium Phosphate, NF (KH2PO4). It contains no
antimicrobial agents. pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 35 mEq potassium, 48 mEq chloride, 20 mEq lactate,
and 15 mEq phosphate as HPO4
=. The osmolarity is 402 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOmsol/L. Administration of substantially hypertonic
solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 189
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized in the liver to glycogen,
and ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is indicated as a source of water, electrolytes and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of lactate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes
and Dextrose Injection, Type 3, USP) can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 190
dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of
solute overloading causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 75
Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) may result in sodium or
potassium retention.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 75 Injection
(Multiple Electrolytes and Dextrose Injection, Type 3, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5%
Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 191
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and
Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). It is also not
known whether 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, USP) can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and
Dextrose Injection, Type 3, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 75
Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
IT IS NOT KNOWN WHETHER THIS DRUG IS EXCRETED IN HUMAN MILK. BECAUSE MANY DRUGS ARE EXCRETED
IN HUMAN MILK, CAUTION SHOULD BE EXERCISED WHEN 5% DEXTROSE AND ELECTROLYTE NO. 75 INJECTION
(MULTIPLE ELECTROLYTES AND DEXTROSE INJECTION, TYPE 3, USP) IS ADMINISTERED TO A NURSING
MOTHER.
Pediatric Use
Safety and effectiveness of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and
Dextrose Injection, Type 3, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of dextrose and electrolyte solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, USP) did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in the responses between elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or
drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 192
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2112
250
NDC 0338-6338-02
6E2113
500
NDC 0338-6338-03
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 193
6E2114
1000
NDC 0338-6338-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 194
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 195
Baxter
3% and 5% Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid
and electrolyte replenishment in single dose containers for intravenous administration. The pH may
have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic
concentration, osmolarity, and pH are shown in Table 1.
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
size
(mL)
Sodium Chloride
USP (NaCl)
Sodium
Chloride
*Osmolarity
(mOsmol/L)
(calc)
pH
3% Sodium
Chloride Injection,
USP
500
30
513
513
1027
5.5
(4.5 to 7.0)
5% Sodium
Chloride Injection,
USP
500
50
856
856
1711
5.5
(4.5 to 7.0)
*Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L)
may cause vein damage.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 196
Clinical Pharmacology
3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is
capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
3% and 5% Sodium Chloride Injection, USP is strongly hypertonic and may cause vein damage.
3% and 5% Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
In patients with diminished renal function, administration of 3% and 5% Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 197
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 3%
and 5% Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 3% and 5% Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 3% and 5%
Sodium Chloride Injection, USP. It is also not known whether 3% and 5% Sodium Chloride Injection,
USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
3% and 5% Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 3% and 5% Sodium Chloride Injection, USP
on labor and delivery. Caution should be exercised when administering this drug during labor and
delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when 3% and 5% Sodium Chloride Injection, USP is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not
been established by adequate and well controlled trials, however, the use of sodium chloride solutions
in the pediatric population is referenced in the medical literature. The warnings, precautions and
adverse reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of 3% and 5% Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 198
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of a final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows:
Code
Size (mL)
NDC
Product Name
6E1353
500
0338-6339-03
3% Sodium
Chloride Injection,
USP
6E1373
500
0338-6340-03
5% Sodium
Chloride Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 199
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 200
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 201
Baxter
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1,
USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic,
hypotonic solution in a single dose container for intravenous administration. Each 100 mL contains
234 mg of Sodium Chloride, USP (NaCl); 128 mg of Potassium Acetate, USP (C2H3KO2); and 32 mg
of Magnesium Acetate Tetrahydrate (Mg(C2H3O2)2•4H2O). It contains no antimicrobial agents. The
pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0).
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a source of water and electrolytes. One liter has an ionic concentration of
40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The
osmolarity is 111 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310
mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 202
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic
alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which
requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of
water and electrolytes or as an alkalinizing agent.
Contraindications
None known
Warnings
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states
in which there exists edema with sodium retention.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium
retention is present.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be
done with great care in those conditions in which there is an increased level or an impaired utilization
of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should not be
administered simultaneously with blood through the same administration set because of the possibility
of hemolysis.
The intravenous administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type
1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 203
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
56 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-
LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 Injection
(Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 204
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE 56 Injection (Multiple Electrolytes
Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) did
not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Do not administer unless solution is clear and seal is intact.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 205
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2524
1000
NDC 0338-6341-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 206
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 207
Baxter
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown below:
Composition (g/L)
Potassium Chloride in
Lactated Ringer’s and
5% Dextrose Injection,
USP
mEq Potassium added
Size
(mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Sodium Lactate, (C3H5NaO3)
Potassium Chloride, USP
(KCl)
Calcium Chloride, USP
(CaCl2•2H2O)
*Osmolarity
(mOsmol/L) (calc.)
20 mEq
1000
50
6
3.1
1.79
0.2
565
40 mEq
1000
50
6
3.1
3.28
0.2
605
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may
cause vein damage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 208
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
Ionic Concentration
(mEq/L)
Potassium Chloride in
Lactated Ringer’s and
5% Dextrose
Injection, USP
mEq Potassium added
pH
Sodium
Potassium
Calcium
Chloride
Lactate
Caloric Content
(kcal/L)
20 mEq
5.0
(3.5 to 6.5)
130
24
3
129
28
170
40 mEq
5.0
(3.5 to 6.5)
130
44
3
149
28
170
** The chemical structure for Dextrose Hydrous, USP is shown below:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 209
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of
water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic
alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which
requires the consumption of hydrogen cations.
Indications and Usage
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of
water, electrolytes, and calories or as alkalinizing agents.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
product.
Warnings
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with metabolic or respiratory alkalosis. The administration of lactate ions
should be done with great care in those conditions in which there is an increased level or an impaired
utilization of these ions, such as severe hepatic insufficiency.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered
with blood through the same administration set because of the likelihood of coagulation.
The intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 210
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in Lactated Ringer’s
and 5% Dextrose Injection, USP may result in sodium or potassium retention.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are not for use in the
treatment of lactic acidosis.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution.
Excess administration may result in metabolic alkalosis.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer’s and 5%
Dextrose Injection, USP to patients receiving corticosteroids or corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 211
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated
Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s
and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5%
Dextrose Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP
in pediatric patients have not been established by adequate and well controlled studies. However, the
use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose in prescribed to pediatric patients, particularly
neonates and low birth weight infants.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Geriatric Use
Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 212
from younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of final filter is recommended during
administration of fall parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers
is available as shown below:
Code
Size (mL)
NDC
Product Name
6E2224
1000
NDC 0338-6344-04
20 mEq/L Potassium
Chloride in Lactated
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 213
Ringer’s and 5%
Dextrose Injection, USP
6E2244
1000
NDC 0338-6345-04
40 mEq/L Potassium
Chloride in Lactated
Ringer’s and 5%
Dextrose Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 214
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:29.024777
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/013684s092,016677s139,et al_lbl.pdf', 'application_number': 18008, 'submission_type': 'SUPPL ', 'submission_number': 65}
|
11,120
|
LITHOBID®
(Lithium Carbonate, USP) Slow-Release Tablets 300 mg
0990
9E Rev 5/2002
LITHOBID®
(Lithium Carbonate, USP) Slow-Release Tablets 300 mg
WARNING
Lithium toxicity is closely related to serum lithium levels, and can occur at doses close
to therapeutic levels. Facilities for prompt and accurate serum lithium determinations
should be available before initiating therapy (see DOSAGE AND ADMINISTRATION).
DESCRIPTION
LITHOBID® Tablets contain lithium carbonate, a white, odorless alkaline powder with molecular
formula Li2CO3 and molecular weight 73.89. Lithium is an element of the alkali-metal group with
atomic number 3, atomic weight 6.94 and an emission line at 671 nm on the flame photometer.
Each peach-colored, film-coated, slow-release tablet contains 300 mg of lithium carbonate. This
slowly dissolving, film-coated tablet is designed to give lower serum lithium peak concentrations
than obtained with conventional oral lithium dosage forms. Inactive ingredients consist of
calcium stearate, carnauba wax, cellulose compounds, FD&C Blue No. 2 Aluminum Lake, FD&C
Red No. 40 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, povidone, propylene glycol,
sodium chloride, sodium lauryl sulfate, sodium starch glycolate, sorbitol and titanium dioxide.
Product meets USP Drug Release Test 1.
ACTIONS
Preclinical studies have shown that lithium alters sodium transport in nerve and muscle cells and
effects a shift toward intraneuronal metabolism of catecholamines, but the specific biochemical
mechanism of lithium action in mania is unknown.
INDICATIONS
Lithium is indicated in the treatment of manic episodes of manic-depressive illness. Maintenance
therapy prevents or diminishes the intensity of subsequent episodes in those manic-depressive
patients with a history of mania.
Typical symptoms: of mania include pressure of speech, motor hyperactivity, reduced need for
sleep, flight of ideas, grandiosity, elation, poor judgment, aggressiveness, and possibly hostility.
When given to a patient experiencing a manic episode, lithium may produce a normalization of
symptomatology within 1 to 3 weeks.
WARNINGS
Lithium should generally not be given to patients with significant renal or cardiovascular disease,
severe debilitation, dehydration, sodium depletion, and to patients receiving diuretics, or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lithobid Package Insert “Draft”
Page 2
angiotensin converting enzyme (ACE) inhibitors, since the risk of lithium toxicity is very high in such
patients. If the psychiatric indication is life threatening, and if such a patient fails to respond to
other measures, lithium treatment may be undertaken with extreme caution, including daily serum
lithium determinations and adjustment to the usually low doses ordinarily tolerated by these
individuals. In such instances, hospitalization is a necessity.
Chronic lithium therapy may be associated with diminution of renal concentrating ability,
occasionally presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia. Such
patients should be carefully managed to avoid dehydration with resulting lithium retention and
toxicity. This condition is usually reversible when lithium is discontinued.
Morphologic changes with glomerular and interstitial fibrosis and nephron atrophy have been
reported in patients on chronic lithium therapy. Morphologic changes have also been seen in
manic-depressive patients never exposed to lithium. The relationship between renal function and
morphologic changes and their association with lithium therapy have not been established.
Kidney function should be assessed prior to and during lithium therapy. Routine urinalysis and
other tests may be used to evaluate tubular function (e.g., urine specific gravity or osmolality
following a period of water deprivation, or 24-hour urine volume) and glomerular function (e.g.,
serum creatinine or creatinine clearance). During lithium therapy, progressive or sudden changes
in renal function, even within the normal range, indicate the need for re-evaluation of treatment.
An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and
confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN and FBS) has
occurred in a few patients treated with lithium plus a neuroleptic, most notably haloperidol. In
some instances, the syndrome was followed by irreversible brain damage. Because of possible
causal relationship between these events and the concomitant administration of lithium and
neuroleptic drugs, patients receiving such combined therapy or patients with organic brain
syndrome or other CNS impairment should be monitored closely for early evidence of neurologic
toxicity and treatment discontinued promptly if such signs appear. This encephalopathic syndrome
may be similar to or the same as Neuroleptic Malignant Syndrome (NMS).
Lithium toxicity is closely related to serum lithium concentrations and can occur at doses close to
the therapeutic concentrations (see DOSAGE AND ADMINISTRATION).
Outpatients and their families should be warned that the patient must discontinue lithium therapy
and contact his physician if such clinical signs of lithium toxicity as diarrhea, vomiting, tremor, mild
ataxia, drowsiness, or muscular weakness occur.
Lithium may prolong the effects of neuromuscular blocking agents. Therefore, neuromuscular
blocking agents should be given with caution to patients receiving lithium.
Usage in Pregnancy
Adverse effects on nidation in rats, embryo viability in mice, and metabolism in vitro of rat testis
and human spermatozoa have been attributed to lithium, as have teratogenicity in submammalian
species and cleft palate in mice.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lithobid Package Insert “Draft”
Page 3
In humans, lithium may cause fetal harm when administered to a pregnant woman. Data from
lithium birth registries suggest an increase in cardiac and other anomalies especially Ebstein's
anomaly. If this drug is used in women of childbearing potential, or during pregnancy, or if a
patient becomes pregnant while taking this drug, the patient should be apprised by their physician
of the potential hazard to the fetus.
Usage in Nursing Mothers
Lithium is excreted in human milk. Nursing should not be undertaken during lithium therapy except
in rare and unusual circumstances where, in the view of the physician, the potential benefits to the
mother outweigh possible hazard to the infant or neonate. Signs and symptoms of lithium toxicity
such as hypertonia, hypothermia, cyanosis and ECG changes have been reported in some infants
and neonates.
Pediatric Use
Safety and effectiveness in pediatric patients under 12 years of age have not been determined; its
use in these patients is not recommended.
There has been a report of transient syndrome of acute dystonia and hyperreflexia occurring in a
15 kg pediatric patient who ingested 300 mg of lithium carbonate.
PRECAUTIONS
The ability to tolerate lithium is greater during the acute manic phase and decreases when manic
symptoms subside (see DOSAGE AND ADMINISTRATION).
The distribution space of lithium approximates that of total body water. Lithium is primarily
excreted in urine with insignificant excretion in feces. Renal excretion of lithium is proportional to
its plasma concentration. The elimination half-life of lithium is approximately 24 hours. Lithium
decreases sodium reabsorption by the renal tubules which could lead to sodium depletion.
Therefore, it is essential for the patient to maintain a normal diet, including salt, and an adequate
fluid intake (2500-3500 mL) at least during the initial stabilization period. Decreased tolerance to
lithium has been reported to ensue from protracted sweating or diarrhea and, if such occur,
supplemental fluid and salt should be administered under careful medical supervision and lithium
intake reduced or suspended until the condition is resolved.
In addition to sweating and diarrhea, concomitant infection with elevated temperatures may also
necessitate a temporary reduction or cessation of medication.
Previously existing thyroid disorders do not necessarily constitute a contraindication to lithium
treatment. Where hypothyroidism preexists, careful monitoring of thyroid function during lithium
stabilization and maintenance allows for correction of changing thyroid parameters and/or
adjustment of lithium doses, if any. If hypothyroidism occurs during lithium stabilization and
maintenance, supplemental thyroid treatment may be used.
In general, the concomitant use of diuretics or angiotensin converting enzyme (ACE) inhibitors with
lithium carbonate should be avoided. In those cases where concomitant use is necessary,
extreme caution is advised since sodium loss from these drugs may reduce the renal clearance of
lithium resulting in increased serum lithium concentrations with the risk of lithium toxicity. When
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lithobid Package Insert “Draft”
Page 4
such combinations are used, the lithium dosage may need to be decreased, and more frequent
monitoring of lithium serum concentrations is recommended. See WARNINGS for additional
caution information.
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side
effects.
The following drugs can lower serum lithium concentrations by increasing urinary lithium excretion:
acetazolamide, urea, xanthine preparations and alkalinizing agents such as sodium bicarbonate.
Concomitant extended use of iodide preparations, especially potassium iodide, with lithium may
produce hypothyroidism.
Concurrent use of calcium channel blocking agents with lithium may increase the risk of
neurotoxicity in the form of ataxia, tremors, nausea, vomiting, diarrhea and/or tinnitus.
Concurrent use of metronidazole with lithium may provoke lithium toxicity due to reduced renal
clearance. Patients receiving such combined therapy should be monitored closely.
Concurrent use of fluoxetine with lithium has resulted in both increased and decreased serum
lithium concentrations. Patients receiving such combined therapy should be monitored closely.
Nonsteroidal anti-inflammatory drugs (NSAIDS): Lithium levels should be closely monitored when
patients initiate or discontinue NSAID use. In some cases, lithium toxicity has resulted from
interactions between an NSAID and lithium. Indomethacin and piroxicam have been reported to
increase significantly steady-state plasma lithium concentrations. There is also evidence that other
nonsteroidal anti-inflammatory agents, including the selective cyclooxygenase-2 (COX2) inhibitors,
have the same effect. In a study conducted in healthy subjects, mean steady-state lithium plasma
levels increased approximately 17% in subjects receiving lithium 450 mg BID with celecoxib 200
mg BID as compared to subjects receiving lithium alone.
Lithium may impair mental and/or physical abilities. Patients should be cautioned about activities
requiring alertness (e.g., operating vehicles or machinery).
Usage in Pregnancy
Pregnancy Category D. (see WARNINGS).
Usage in Nursing Mothers
Because of the potential for serious adverse reactions in nursing infants and neonates from lithium,
a decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother (see WARNINGS).
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 12 have not been established (see
WARNINGS).
Usage in the Elderly Geriatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lithobid Package Insert “Draft”
Page 5
Elderly patients often require lower lithium dosages to achieve therapeutic serum concentrations.
They may also exhibit adverse reactions at serum concentrations ordinarily tolerated by younger
patients. Additionally, patients with renal impairment may also require lower lithium doses (see
WARNINGS). Clinical studies of LITHOBID® did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the
low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other therapy.
ADVERSE REACTIONS
The occurrence and severity of adverse reactions are generally directly related to serum lithium
concentrations and to individual patient sensitivity to lithium. They generally occur more frequently
and with greater severity at higher concentrations.
Adverse reactions may be encountered at serum lithium concentrations below 1.5 mEq/L. Mild to
moderate adverse reactions may occur at concentrations from 1.5-2.5 mEq/L, and moderate to
severe reactions may be seen at concentrations from 2.0 mEq/L and above.
Fine hand tremor, polyuria and mild thirst may occur during initial therapy for the acute manic
phase and may persist throughout treatment. Transient and mild nausea and general discomfort
may also appear during the first few days of lithium administration.
These side effects usually subside with continued treatment or with a temporary reduction or
cessation of dosage. If persistent, a cessation of lithium therapy may be required. Diarrhea,
vomiting, drowsiness, muscular weakness and lack of coordination may be early signs of lithium
intoxication, and can occur at lithium concentrations below 2.0 mEq/L. At higher concentrations,
giddiness, ataxia, blurred vision, tinnitus and a large output of dilute urine may be seen. Serum
lithium concentrations above 3.0 mEq/L may produce a complex clinical picture involving multiple
organs and organ systems. Serum lithium concentrations should not be permitted to exceed 2.0
mEq/L during the acute treatment phase.
The following reactions have been reported and appear to be related to serum lithium
concentrations, including concentrations within the therapeutic range:
Central Nervous System: tremor, muscle hyperirritability (fasciculations, twitching, clonic
movements of whole limbs), hypertonicity, ataxia, choreoathetotic movements, hyperactive deep
tendon reflex, extrapyramidal symptoms including acute dystonia, cogwheel rigidity, blackout
spells, epileptiform seizures, slurred speech, dizziness, vertigo, downbeat nystagmus, incontinence
of urine or feces, somnolence, psychomotor retardation, restlessness, confusion, stupor, coma,
tongue movements, tics, tinnitus, hallucinations, poor memory, slowed intellectual functioning,
startled response, worsening of organic brain syndromes. Cases of Pseudotumor Cerebri
(increased intracranial pressure and papilledema) have been reported with lithium use. If
undetected, this condition may result in enlargement of the blind spot, constriction of visual fields
and eventual blindness due to optic atrophy. Lithium should be discontinued, if clinically possible,
if this syndrome occurs.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lithobid Package Insert “Draft”
Page 6
Cardiovascular: cardiac arrhythmia, hypotension, peripheral circulatory collapse, bradycardia,
sinus node dysfunction with severe bradycardia (which may result in syncope);
Gastrointestinal: anorexia, nausea, vomiting, diarrhea, gastritis, salivary gland swelling,
abdominal pain, excessive salivation, flatulence, indigestion;
Genitourinary: glycosuria, decreased creatinine clearance, albuminuria, oliguria, and symptoms
of nephrogenic diabetes insipidus including polyuria, thirst and polydipsia;
Dermatologic: drying and thinning of hair, alopecia, anesthesia of skin, acne, chronic folliculitis,
xerosis cutis, psoriasis or its exacerbation, generalized pruritus with or without rash, cutaneous
ulcers, angioedema;
Autonomic Nervous System: blurred vision, dry mouth, impotence/sexual dysfunction;
Thyroid Abnormalities: euthyroid goiter and/or hypothyroidism (including myxedema)
accompanied by lower T3 and T4. 131Iodine uptake may be elevated (see PRECAUTIONS).
Paradoxically, rare cases of hyperthyroidism have been reported.
EEG Changes: diffuse slowing, widening of frequency spectrum, potentiation and disorganization
of background rhythm.
EKG Changes: reversible flattening, isoelectricity or inversion of T-waves.
Miscellaneous: Fatigue, lethargy, transient scotomata, exophthalmos, dehydration, weight loss,
leucocytosis, headache, transient hyperglycemia, hypercalcemia, hyperparathyroidism,
albuminuria, excessive weight gain, edematous swelling of ankles or wrists, metallic taste,
dysgeusia/taste distortion, salty taste, thirst, swollen lips, tightness in chest, swollen and/or painful
joints, fever, polyarthralgia, and dental caries.
Some reports of nephrogenic diabetes insipidus, hyperparathyroidism and hypothyroidism which
persist after lithium discontinuation have been received.
A few reports have been received of the development of painful discoloration of fingers and toes
and coldness of the extremities within one day of starting lithium treatment. The mechanism
through which these symptoms (resembling Raynaud's Syndrome) developed is not known.
Recovery followed discontinuance.
DOSAGE AND ADMINISTRATION
Acute Mania
Optimal patient response can usually be established with 1800 mg/day in the following dosages:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lithobid Package Insert “Draft”
Page 7
ACUTE MANIA
Morning
Afternoon
Nighttime
LITHOBID® Slow-
Release Tablets1
3 tabs
(900 mg)
3 tabs
(900 mg)
1Can also be administered on 600 mg t.i.d. recommended dosing interval.
Such doses will normally produce an effective serum lithium concentration ranging between 1.0
and 1.5 mEq/L. Dosage must be individualized according to serum concentrations and clinical
response. Regular monitoring of the patient's clinical state and of serum lithium concentrations is
necessary. Serum concentrations should be determined twice per week during the acute phase,
and until the serum concentrations and clinical condition of the patient have been stabilized.
Long-Term Control
Desirable serum lithium concentrations are 0.6 to 1.2 mEq/L which can usually be achieved with
900-1200 mg/day. Dosage will vary from one individual to another, but generally the following
dosages will maintain this concentration.
LONG TERM
Morning
Afternoon
Nighttime
LITHOBID® Slow-Release
Tablets1
2 tabs
(600 mg)
2 tabs
(600 mg)
1Can be administered on t.i.d. recommended dosing interval up to 1200 mg/day.
Serum lithium concentrations in uncomplicated cases receiving maintenance therapy during
remission should be monitored at least every two months. Patients abnormally sensitive to lithium
may exhibit toxic signs at serum concentrations of 1.0 to 1.5 mEq/L. Elderly Geriatric patients
often respond to reduced dosage, and may exhibit signs of toxicity at serum concentrations
ordinarily tolerated by other patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
N.B.: Blood samples for serum lithium determinations should be drawn immediately prior to the
next dose when lithium concentrations are relatively stable (i.e., 8-12 hours after previous dose).
Total reliance must not be placed on serum concentrations alone. Accurate patient evaluation
requires both clinical and laboratory analysis.
LITHOBID® Slow-Release Tablets must be swallowed whole and never chewed or crushed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lithobid Package Insert “Draft”
Page 8
OVERDOSAGE
The toxic concentrations for lithium (≥1.5 mEq/L) are close to the therapeutic concentrations (0.6-
1.2 mEq/L). It is therefore important that patients and their families be cautioned to watch for early
toxic symptoms and to discontinue the drug and inform the physician should they occur. (Toxic
symptoms are listed in detail under ADVERSE REACTIONS.)
Treatment
No specific antidote for lithium poisoning is known. Treatment is supportive. Early symptoms of
lithium toxicity can usually be treated by reduction or cessation of dosage of the drug and
resumption of the treatment at a lower dose after 24 to 48 hours. In severe cases of lithium
poisoning, the first and foremost goal of treatment consists of elimination of this ion from the
patient.
Treatment is essentially the same as that used in barbiturate poisoning: 1) gastric lavage, 2)
correction of fluid and electrolyte imbalance and, 3) regulation of kidney functioning. Urea,
mannitol, and aminophylline all produce significant increases in lithium excretion. Hemodialysis is
an effective and rapid means of removing the ion from the severely toxic patient. However, patient
recovery may be slow.
Infection prophylaxis, regular chest X-rays, and preservation of adequate respiration are essential.
HOW SUPPLIED
LITHOBID® (Lithium Carbonate, USP) Slow-Release Tablets, 300 mg, peach-colored imprinted
“SOLVAY 4492”
Bottles of 100
NDC 0032-4492-01
Bottles of 1000
NDC 0032-4492-10
Store between 59°-86°F (15°-30°C). Protect from moisture. Dispense in tight, child-resistant
container (USP).
Solvay
Pharmaceuticals, Inc.
Marietta, GA 30062
0990
9E Rev 5/2002
© 2002 Solvay Pharmaceuticals, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Russell Katz
10/7/02 07:54:35 AM
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18027s40s46s49lbl.pdf', 'application_number': 18027, 'submission_type': 'SUPPL ', 'submission_number': 49}
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LITHOBID® (Lithium Carbonate, USP)
Extended-Release Tablets 300 mg
Rev month/year
Rx only
WARNING
Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic levels.
Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy
(see DOSAGE AND ADMINISTRATION).
DESCRIPTION
LITHOBID® tablets contain lithium carbonate, a white odorless alkaline powder with molecular formula
Li2CO3 and molecular weight 73.89. Lithium is an element of the alkali-metal group with atomic number 3,
atomic weight 6.94, and an emission line at 671 nm on the flame photometer. Each peach-colored, film-coated,
extended-release tablet contains 300 mg of lithium carbonate. This slowly dissolving film-coated tablet is
designed to give lower serum lithium peak concentrations than obtained with conventional oral lithium dosage
forms. Inactive ingredients consist of calcium stearate, carnauba wax, cellulose compounds, FD&C Blue No. 2
Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, povidone,
propylene glycol, sodium chloride, sodium lauryl sulfate, sodium starch glycolate, sorbitol, and titanium
dioxide. Product meets USP Drug Release Test 1.
ACTIONS
Preclinical studies have shown that lithium alters sodium transport in nerve and muscle cells and effects a shift
toward intraneuronal metabolism of catecholamines, but the specific biochemical mechanism of lithium action
in mania is unknown.
INDICATIONS
LITHOBID® (lithium carbonate) is indicated in the treatment of manic episodes of Bipolar Disorder. Bipolar
Disorder, Manic (DSM-IV) is equivalent to Manic Depressive illness, Manic, in the older DSM-II terminology.
LITHOBID® is also indicated as a maintenance treatment for individuals with a diagnosis of Bipolar Disorder.
Maintenance therapy reduces the frequency of manic episodes and diminishes the intensity of those episodes
which may occur.
Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of
ideas, grandiosity, elation, poor judgment, aggressiveness, and possibly hostility. When given to a patient
experiencing a manic episode, lithium may produce a normalization of symptomatology within 1 to 3 weeks.
WARNINGS
Lithium Toxicity
Lithium toxicity is closely related to serum lithium concentrations and can occur at doses close to therapeutic
concentrations (see DOSAGE AND ADMINISTRATION).
Outpatients and their families should be warned that the patient must discontinue lithium therapy and contact
his physician if such clinical signs of lithium toxicity as diarrhea, vomiting, tremor, mild ataxia, drowsiness, or
muscular weakness occur.
Lithium should generally not be given to patients with significant renal or cardiovascular disease, severe
debilitation, dehydration, sodium depletion, and to patients receiving diuretics, or angiotensin converting
enzyme (ACE) inhibitors, since the risk of lithium toxicity is very high in such patients. If the psychiatric
Reference ID: 3031562
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indication is life threatening, and if such a patient fails to respond to other measures, lithium treatment may be
undertaken with extreme caution, including daily serum lithium determinations and adjustment to the usually
low doses ordinarily tolerated by these individuals. In such instances, hospitalization is a necessity.
Unmasking of Brugada Syndrome
There have been postmarketing reports of a possible association between treatment with lithium and the
unmasking of Brugada Syndrome. Brugada Syndrome is a disorder characterized by abnormal
electrocardiographic (ECG) findings and a risk of sudden death. Lithium should generally be avoided in patients
with Brugada Syndrome or those suspected of having Brugada Syndrome. Consultation with a cardiologist is
recommended if: (1) treatment with lithium is under consideration for patients suspected of having Brugada
Syndrome or patients who have risk factors for Brugada Syndrome, e.g., unexplained syncope, a family history
of Brugada Syndrome, or a family history of sudden unexplained death before the age of 45 years, (2) patients
who develop unexplained syncope or palpitations after starting lithium therapy.
Renal Effects
Chronic lithium therapy may be associated with diminution of renal concentrating ability, occasionally
presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia. Such patients should be carefully
managed to avoid dehydration with resulting lithium retention and toxicity. This condition is usually reversible
when lithium is discontinued.
Morphologic changes with glomerular and interstitial fibrosis and nephron atrophy have been reported in
patients on chronic lithium therapy. Morphologic changes have also been seen in manic-depressive patients
never exposed to lithium. The relationship between renal function and morphologic changes and their
association with lithium therapy have not been established.
Kidney function should be assessed prior to and during lithium therapy. Routine urinalysis and other tests may
be used to evaluate tubular function (e.g., urine specific gravity or osmolality following a period of water
deprivation, or 24-hour urine volume) and glomerular function (e.g., serum creatinine or creatinine clearance).
During lithium therapy, progressive or sudden changes in renal function, even within the normal range, indicate
the need for reevaluation of treatment.
Encephalopathic Syndrome
An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion,
extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and FBS) has occurred in a few
patients treated with lithium plus a neuroleptic, most notably haloperidol. In some instances, the syndrome was
followed by irreversible brain damage. Because of possible causal relationship between these events and the
concomitant administration of lithium and neuroleptic drugs, patients receiving such combined therapy or
patients with organic brain syndrome or other CNS impairment should be monitored closely for early evidence
of neurologic toxicity and treatment discontinued promptly if such signs appear. This encephalopathic
syndrome may be similar to or the same as Neuroleptic Malignant Syndrome (NMS).
Concomitant Use with Neuromuscular Blocking Agents
Lithium may prolong the effects of neuromuscular blocking agents. Therefore, neuromuscular blocking agents
should be given with caution to patients receiving lithium.
Usage in Pregnancy
Reference ID: 3031562
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Adverse effects on nidationin rats, embryo viability in mice, and metabolism in vitro of rat testis and human
spermatozoa have been attributed to lithium, as have teratogenicity in submammalian species and cleft palate in
mice.
In humans, lithium may cause fetal harm when administered to a pregnant woman. Data from lithium birth
registries suggest an increase in cardiac and other anomalies, especially Ebstein's anomaly. If this drug is used
in women of childbearing potential, or during pregnancy, or if a patient becomes pregnant while taking this
drug, the patient should be apprised by their physician of the potential hazard to the fetus.
Usage in Nursing Mothers
Lithium is excreted in human milk. Nursing should not be undertaken during lithium therapy except in rare and
unusual circumstances where, in the view of the physician, the potential benefits to the mother outweigh
possible hazard to the infant or neonate. Signs and symptoms of lithium toxicity such as hypertonia,
hypothermia, cyanosis, and ECG changes have been reported in some infants and neonates.
Pediatric Use
Safety and effectiveness in pediatric patients under 12 years of age have not been determined; its use in these
patients is not recommended.
There has been a report of transient syndrome of acute dystonia and hyperreflexia occurring in a 15 kg pediatric
patient who ingested 300 mg of lithium carbonate.
PRECAUTIONS
The ability to tolerate lithium is greater during the acute manic phase and decreases when manic symptoms
subside (see DOSAGE AND ADMINISTRATION).
The distribution space of lithium approximates that of total body water. Lithium is primarily excreted in urine
with insignificant excretion in feces. Renal excretion of lithium is proportional to its plasma concentration. The
elimination half-life of lithium is approximately 24 hours. Lithium decreases sodium reabsorption by the renal
tubules which could lead to sodium depletion. Therefore, it is essential for the patient to maintain a normal diet,
including salt, and an adequate fluid intake (2500-3500 mL) at least during the initial stabilization period.
Decreased tolerance to lithium has been reported to ensue from protracted sweating or diarrhea and, if such
occur, supplemental fluid and salt should be administered under careful medical supervision and lithium intake
reduced or suspended until the condition is resolved.
In addition to sweating and diarrhea, concomitant infection with elevated temperatures may also necessitate a
temporary reduction or cessation of medication.
Previously existing thyroid disorders do not necessarily constitute a contraindication to lithium treatment.
Where hypothyroidism preexists, careful monitoring of thyroid function during lithium stabilization and
maintenance allows for correction of changing thyroid parameters and/or adjustment of lithium doses, if any. If
hypothyroidism occurs during lithium stabilization and maintenance, supplemental thyroid treatment may be
used. In general, the concomitant use of diuretics or angiotensin converting enzyme (ACE) inhibitors with
lithium carbonate should be avoided. In those cases where concomitant use is necessary, extreme caution is
advised since sodium loss from these drugs may reduce the renal clearance of lithium resulting in increased
serum lithium concentrations with the risk of lithium toxicity. When such combinations are used, the lithium
dosage may need to be decreased, and more frequent monitoring of lithium serum concentrations is
recommended. See WARNINGS for additional caution information.
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
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The following drugs can lower serum lithium concentrations by increasing urinary lithium excretion:
acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate.
Concomitant extended use of iodide preparations, especially potassium iodide, with lithium may produce
hypothyroidism.
Concurrent use of calcium channel blocking agents with lithium may increase the risk of neurotoxicity in the
form of ataxia, tremors, nausea, vomiting, diarrhea, and/or tinnitus.
Concurrent use of metronidazole with lithium may provoke lithium toxicity due to reduced renal clearance.
Patients receiving such combined therapy should be monitored closely.
Concurrent use of fluoxetine with lithium has resulted in both increased and decreased serum lithium
concentrations. Patients receiving such combined therapy should be monitored closely.
Nonsteroidal anti-inflammatory drugs (NSAIDs): Lithium levels should be closely monitored when patients
initiate or discontinue NSAID use. In some cases, lithium toxicity has resulted from interactions between a
NSAID and lithium. Indomethacin and piroxicam have been reported to increase significantly steady-state
plasma lithium concentrations. There is also evidence that other nonsteroidal anti-inflammatory agents,
including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect. In a study conducted in
healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving
lithium 450 mg BID with celecoxib 200 mg BID as compared to subjects receiving lithium alone.
Lithium may impair mental and/or physical abilities. Patients should be cautioned about activities requiring
alertness (e.g., operating vehicles or machinery).
Usage in Pregnancy
Pregnancy Category D. (See WARNINGS.)
Usage in Nursing Mothers
Because of the potential for serious adverse reactions in nursing infants and neonates from lithium, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of
the drug to the mother (see WARNINGS).
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 12 have not been established (see WARNINGS).
Geriatric Use
Clinical studies of LITHOBID® tablets did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be
greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
The occurrence and severity of adverse reactions are generally directly related to serum lithium concentrations
and to individual patient sensitivity to lithium. They generally occur more frequently and with greater severity
at higher concentrations.
Reference ID: 3031562
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Adverse reactions may be encountered at serum lithium concentrations below 1.5 mEq/L. Mild to moderate
adverse reactions may occur at concentrations from 1.5-2.5 mEq/L, and moderate to severe reactions may be
seen at concentrations from 2.0 mEq/L and above.
Fine hand tremor, polyuria, and mild thirst may occur during initial therapy for the acute manic phase and may
persist throughout treatment. Transient and mild nausea and general discomfort may also appear during the first
few days of lithium administration.
These side effects usually subside with continued treatment or with a temporary reduction or cessation of
dosage. If persistent, a cessation of lithium therapy may be required. Diarrhea, vomiting, drowsiness, muscular
weakness, and lack of coordination may be early signs of lithium intoxication, and can occur at lithium
concentrations below 2.0 mEq/L. At higher concentrations, giddiness, ataxia, blurred vision, tinnitus, and a
large output of dilute urine may be seen. Serum lithium concentrations above 3.0 mEq/L may produce a
complex clinical picture involving multiple organs and organ systems. Serum lithium concentrations should not
be permitted to exceed 2.0 mEq/L during the acute treatment phase.
The following reactions have been reported and appear to be related to serum lithium concentrations, including
concentrations within the therapeutic range:
Central Nervous System: tremor, muscle hyperirritability (fasciculations, twitching, clonic movements of
whole limbs), hypertonicity, ataxia, choreoathetotic movements, hyperactive deep tendon reflex, extrapyramidal
symptoms including acute dystonia, cogwheel rigidity, blackout spells, epileptiform seizures, slurred speech,
dizziness, vertigo, downbeat nystagmus, incontinence of urine or feces, somnolence, psychomotor retardation,
restlessness, confusion, stupor, coma, tongue movements, tics, tinnitus, hallucinations, poor memory, slowed
intellectual functioning, startled response, worsening of organic brain syndromes. Cases of Pseudotumor cerebri
(increased intracranial pressure and papilledema) have been reported with lithium use. If undetected, this
condition may result in enlargement of the blind spot, constriction of visual fields, and eventual blindness due to
optic atrophy. Lithium should be discontinued, if clinically possible, if this syndrome occurs. Cardiovascular:
cardiac arrhythmia, hypotension, peripheral circulatory collapse, bradycardia, sinus node dysfunction with
severe bradycardia (which may result in syncope), Unmasking of Brugada Syndrome [See WARNINGS and
PATIENT COUNSELING INFORMATION]. Gastrointestinal: anorexia, nausea, vomiting, diarrhea,
gastritis, salivary gland swelling, abdominal pain, excessive salivation, flatulence, indigestion. Genitourinary:
glycosuria, decreased creatinine clearance, albuminuria, oliguria, and symptoms of nephrogenic diabetes
insipidus including polyuria, thirst and polydipsia. Dermatologic: drying and thinning of hair, alopecia,
anesthesia of skin, acne, chronic folliculitis, xerosis cutis, psoriasis or its exacerbation, generalized pruritus with
or without rash, cutaneous ulcers, angioedema, Autonomic Nervous System: blurred vision, dry mouth,
impotence/ sexual dysfunction. Thyroid Abnormalities: euthyroid goiter and/or hypothyroidism (including
myxedema) accompanied by lower T3 and T4. 131Iodine uptake may be elevated (see PRECAUTIONS).
Paradoxically, rare cases of hyperthyroidism have been reported. EEG Changes: diffuse slowing, widening of
frequency spectrum, potentiation and disorganization of background rhythm. EKG Changes: reversible
flattening, isoelectricity or inversion of T-waves. Miscellaneous: fatigue, lethargy, transient scotomata,
exophthalmos, dehydration, weight loss, leucocytosis, headache, transient-hyperglycemia, hypercalcemia,
hyperparathyroidism, albuminuria, excessive weight gain, edematous swelling of ankles or wrists, metallic
taste, dysgeusia/taste distortion, salty taste, thirst, swollen lips, tightness in chest, swollen and/or painful joints,
fever, polyarthralgia, and dental caries.
Some reports of nephrogenic diabetes insipidus, hyperparathyroidism, and hypothyroidism which persist after
lithium discontinuation have been received.
A few reports have been received of the development of painful discoloration of fingers and toes and coldness
of the extremities within one day of starting lithium treatment. The mechanism through which these symptoms
(resembling Raynaud's Syndrome) developed is not known. Recovery followed discontinuance.
Reference ID: 3031562
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DOSAGE AND ADMINISTRATION
Acute Mania
Optimal patient response can usually be established with 1800 mg/day in the following dosages:
Acute Mania
Morning
Afternoon
Nighttime
LITHOBID®
3 tabs
3 tabs
Extended-Release Tablets1
(900 mg)
(900 mg)
1Can also be administered on 600 mg TID recommended dosing interval.
Such doses will normally produce an effective serum lithium concentration ranging between 1.0 and 1.5 mEq/L.
Dosage must be individualized according to serum concentrations and clinical response. Regular monitoring of
the patient's clinical state and of serum lithium concentrations is necessary. Serum concentrations should be
determined twice per week during the acute phase, and until the serum concentrations and clinical condition of
the patient have been stabilized.
Long-Term Control
Desirable serum lithium concentrations are 0.6 to 1.2 mEq/L which can usually be achieved with 900-1200
mg/day. Dosage will vary from one individual to another, but generally the following dosages will maintain this
concentration:
Long-Term Control
Morning
Afternoon
Nighttime
LITHOBID®
2 tabs
2 tabs
Extended-Release Tablets1
(600 mg)
(600 mg)
1Can be administered on TID recommended dosing interval up to 1200 mg/day.
Serum lithium concentrations in uncomplicated cases receiving maintenance therapy during remission should be
monitored at least every two months. Patients abnormally sensitive to lithium may exhibit toxic signs at serum
concentrations of 1.0 to 1.5 mEq/L. Geriatric patients often respond to reduced dosage, and may exhibit signs of
toxicity at serum concentrations ordinarily tolerated by other patients. In general, dose selection for an elderly
patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Important Considerations
• Blood samples for serum lithium determinations should be drawn immediately prior to the next dose
when lithium concentrations are relatively stable (i.e., 8-12 hours after previous dose). Total reliance
must not be placed on serum concentrations alone. Accurate patient evaluation requires both clinical and
laboratory analysis.
• LITHOBID® Extended-Release Tablets must be swallowed whole and never chewed or crushed.
OVERDOSAGE
The toxic concentrations for lithium (1.5 mEq/ L) are close to the therapeutic concentrations (0.6-1.2 mEq/L). It
is therefore important that patients and their families be cautioned to watch for early toxic symptoms and to
discontinue the drug and inform the physician should they occur. (Toxic symptoms are listed in detail under
ADVERSE REACTIONS.)
Reference ID: 3031562
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c
ompany logo
Treatment
No specific antidote for lithium poisoning is known. Treatment is supportive. Early symptoms of lithium
toxicity can usually be treated by reduction or cessation of dosage of the drug and resumption of the treatment
at a lower dose after 24 to 48 hours. In severe cases of lithium poisoning, the first and foremost goal of
treatment consists of elimination of this ion from the patient.
Treatment is essentially the same as that used in barbiturate poisoning: 1) gastric lavage, 2) correction of fluid
and electrolyte imbalance and, 3) regulation of kidney functioning. Urea, mannitol, and aminophylline all
produce significant increases in lithium excretion. Hemodialysis is an effective and rapid means of removing
the ion from the severely toxic patient. However, patient recovery may be slow.
Infection prophylaxis, regular chest X-rays, and preservation of adequate respiration are essential.
PATIENT COUNSELING INFORMATION
Information for Patients: A condition known as Brugada Syndrome may pre-exist and be unmasked by lithium
therapy. Brugada Syndrome is a heart disorder characterized by abnormal electrocardiographic (ECG) findings
and risk of sudden death. Patients should be advised to seek immediate emergency assistance if they experience
fainting, lightheadedness, abnormal heart beats, or shortness of breath because they may have a potentially life-
threatening heart disorder known as Brugada Syndrome.
HOW SUPPLIED
LITHOBID® (Lithium Carbonate, USP)
Extended-Release Tablets, 300 mg, peach-colored imprinted “LITHOBID 300”
NDC 68968-4492-1
(Bottle of 100)
Storage Conditions
Store between 59°-86°F (15°-30°C). Protect from moisture. Dispense in tight, child-resistant container (USP).
LITHOBID
®
(Lithium Carbonate, USP)
Print Date: Month/year
© 2009 Noven Therapeutics, LLC
Reference ID: 3031562
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018027s056lbl.pdf', 'application_number': 18027, 'submission_type': 'SUPPL ', 'submission_number': 56}
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T2006-56
Ritalin® hydrochloride
methylphenidate hydrochloride
tablets USP
Ritalin-SR®
methylphenidate hydrochloride USP
sustained-release tablets
Rx only
Prescribing Information
DESCRIPTION
Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS)
stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as
sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl
α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions
are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble
in chloroform and in acetone. Its molecular weight is 269.77.
Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C
Green No. 3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and
10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets).
Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate,
mineral oil, povidone, titanium dioxide, and zein.
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Page 2
CLINICAL PHARMACOLOGY
Ritalin is a mild central nervous system stimulant.
The mode of action in man is not completely understood, but Ritalin presumably activates the
brain stem arousal system and cortex to produce its stimulant effect.
There is neither specific evidence which clearly establishes the mechanism whereby Ritalin
produces its mental and behavioral effects in children, nor conclusive evidence regarding how these
effects relate to the condition of the central nervous system.
Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets.
Relative bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary
excretion of Ritalin major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in
children and 101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2
hours) for the SR tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet
dose was excreted in children as compared to 86% in adults.
In a clinical study involving adult subjects who received SR tablets, plasma concentrations of
Ritalin’s major metabolite appeared to be greater in females than in males. No gender differences were
observed for Ritalin plasma concentration in the same subjects.
INDICATIONS
Attention Deficit Disorders, Narcolepsy
Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other
terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome,
Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction.
Ritalin is indicated as an integral part of a total treatment program which typically includes
other remedial measures (psychological, educational, social) for a stabilizing effect in children with a
behavioral syndrome characterized by the following group of developmentally inappropriate
symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability,
and impulsivity. The diagnosis of this syndrome should not be made with finality when these
symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning
disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system
dysfunction may or may not be warranted.
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Page 3
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate
diagnosis requires the use not only of medical but of special psychological, educational, and social
resources.
Characteristics commonly reported include: chronic history of short attention span,
distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor
neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be
based upon a complete history and evaluation of the child and not solely on the presence of one or
more of these characteristics.
Drug treatment is not indicated for all children with this syndrome. Stimulants are not
intended for use in the child who exhibits symptoms secondary to environmental factors and/or
primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and
psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the
decision to prescribe stimulant medication will depend upon the physician’s assessment of the
chronicity and severity of the child’s symptoms.
CONTRAINDICATIONS
Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate
these symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in
patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of
Tourette’s syndrome.
Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within
a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive
crises may result).
WARNINGS
Serious Cardiovascular Events
Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other
Serious Heart Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in
children and adolescents with structural cardiac abnormalities or other serious heart problems.
Although some serious heart problems alone carry an increased risk of sudden death,
stimulant products generally should not be used in children or adolescents with known serious
structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4
serious cardiac problems that may place them at increased vulnerability to the
sympathomimetic effects of a stimulant drug.
Adults
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant
drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also
unknown, adults have a greater likelihood than children of having serious structural cardiac
abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease,
or other serious cardiac problems. Adults with such abnormalities should also generally not be
treated with stimulant drugs.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg)
and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the
mean changes alone would not be expected to have short-term consequences, all patients
should be monitored for larger changes in heart rate and blood pressure. Caution is indicated
in treating patients whose underlying medical conditions might be compromised by increases
in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent
myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant
Medications
Children, adolescents, or adults who are being considered for treatment with stimulant
medications should have a careful history (including assessment for a family history of
sudden death or ventricular arrhythmia) and physical exam to assess for the presence of
cardiac disease, and should receive further cardiac evaluation if findings suggest such disease
(e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as
exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease
during stimulant treatment should undergo a prompt cardiac evaluation.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought
disorder in patients with a pre-existing psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid
bipolar disorder because of concern for possible induction of a mixed/ manic episode in such
patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive
symptoms should be adequately screened to determine if they are at risk for bipolar disorder;
such screening should include a detailed psychiatric history, including a family history of
suicide, bipolar disorder, and depression.
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Page 5
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking,
or mania in children and adolescents without a prior history of psychotic illness or mania can
be caused by stimulants at usual doses. If such symptoms occur, consideration should be
given to a possible causal role of the stimulant, and discontinuation of treatment may be
appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such
symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to
methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated
patients compared to 0 in placebo-treated patients.
Aggression
Aggressive behavior or hostility is often observed in children and adolescents with ADHD,
and has been reported in clinical trials and the postmarketing experience of some medications
indicated for the treatment of ADHD. Although there is no systematic evidence that
stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD
should be monitored for the appearance of or worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to
either methylphenidate or non-medication treatment groups over 14 months, as well as in
naturalistic subgroups of newly methylphenidate-treated and non-medication treated children
over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children
(i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth
rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight
over 3 years), without evidence of growth rebound during this period of development.
Published data are inadequate to determine whether chronic use of amphetamines may cause a
similar suppression of growth, however, it is anticipated that they likely have this effect as
well. Therefore, growth should be monitored during treatment with stimulants, and patients
who are not growing or gaining height or weight as expected may need to have their treatment
interrupted.
Seizures
There is some clinical evidence that stimulants may lower the convulsive threshold in patients
with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures,
and, very rarely, in patients without a history of seizures and no prior EEG evidence of
seizures. In the presence of seizures, the drug should be discontinued.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant
treatment.
Use in Children Under Six Years of Age
Ritalin should not be used in children under 6 years, since safety and efficacy in this age
group have not been established.
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Drug Dependence
Ritalin should be given cautiously to patients with a history of drug dependence or
alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence
with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially
with parenteral abuse. Careful supervision is required during withdrawal from abusive use,
since severe depression may occur. Withdrawal following chronic therapeutic use may
unmask symptoms of the underlying disorder that may require follow-up.
PRECAUTIONS
Patients with an element of agitation may react adversely; discontinue therapy if necessary.
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Drug treatment is not indicated in all cases of this behavioral syndrome and should be
considered only in light of the complete history and evaluation of the child. The decision to prescribe
Ritalin should depend on the physician’s assessment of the chronicity and severity of the child’s
symptoms and their appropriateness for his/her age. Prescription should not depend solely on the
presence of one or more of the behavioral characteristics.
When these symptoms are associated with acute stress reactions, treatment with Ritalin is
usually not indicated.
Drug Interactions
Ritalin should not be used in patients being treated (currently or within the proceeding two
weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors).
Because of possible effects on blood pressure, Ritalin should be used cautiously with pressor
agents.
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension.
Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through
oxidative pathways.
Human pharmacologic studies have shown that racemic methylphenidate may inhibit the
metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin,
primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward
dose adjustments of these drugs may be required when given concomitantly with
methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug
concentration (or, in case of coumarin, coagulation times), when initiating or discontinuing
methylphenidate.
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Serious adverse events have been reported in concomitant use with clonidine, although no
causality for the combination has been established. The safety of using methylphenidate in
combination with clonidine or other centrally acting alpha-2-agonists has not been
systematically evaluated.
Carcinogenesis/Mutagenesis/Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in
hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of
approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum
recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively
rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse
strain used is sensitive to the development of hepatic tumors, and the significance of these results to
humans is unknown.
Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study
carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is
approximately 22 times and 5 times the maximum recommended human dose on a mg/kg and mg/m2
basis, respectively.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to
genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets
containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the
high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in
vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome
aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured
Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in
the mouse bone marrow micronucleus assay.
Methlyphenidate did not impair fertility in male or female mice that were fed diets containing
the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to
160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and
mg/m2 basis, respectively.
PREGNANCY
Pregnancy Category C
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75
and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased
incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40
times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for
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embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There
was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal
variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also
maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times
the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy
and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest
dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were
observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to
the MRHD on a mg/m2 basis).
Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised if Ritalin is administered to a nursing woman.
Pediatric Use
Ritalin should not be used in children under six years of age (see WARNINGS).
In a study conducted in young rats, methylphenidate was administered orally at doses of up to
100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing
through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal
Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females
previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose
[MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was
seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect
level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2
basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
ADVERSE REACTIONS
Nervousness and insomnia are the most common adverse reactions but are usually controlled by
reducing dosage and omitting the drug in the afternoon or evening. Other reactions include
hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema
multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura);
anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse
changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss
during prolonged therapy. There have been rare reports of Tourette’s syndrome. Toxic psychosis has
been reported. Although a definite causal relationship has not been established, the following have
been reported in patients taking this drug: instances of abnormal liver function, ranging from
transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion;
leukopenia and/or anemia; transient depressed mood; aggressive behavior; a few instances of scalp
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Page 9
hair loss. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in
most of these, patients were concurrently receiving therapies associated with NMS. In a single report,
a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an
NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether
this case represented a drug-drug interaction, a response to either drug alone, or some other cause.
In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia,
and tachycardia may occur more frequently; however, any of the other adverse reactions listed above
may also occur.
DOSAGE AND ADMINISTRATION
Dosage should be individualized according to the needs and responses of the patient.
Adults
Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals.
Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to
15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day
should take the last dose before 6 p.m.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore,
Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR
corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and
never crushed or chewed.
Children (6 years and over)
Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg
is not recommended.
If improvement is not observed after appropriate dosage adjustment over a one-month period,
the drug should be discontinued.
Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5
to 10 mg weekly.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore,
Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR
corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and
never crushed or chewed.
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If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if
necessary, discontinue the drug.
Ritalin should be periodically discontinued to assess the child’s condition. Improvement may
be sustained when the drug is either temporarily or permanently discontinued.
Drug treatment should not and need not be indefinite and usually may be discontinued after
puberty.
OVERDOSAGE
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central
nervous system and from excessive sympathomimetic effects, may include the following: vomiting,
agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria,
confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia,
palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance
and advice.
Treatment consists of appropriate supportive measures. The patient must be protected against
self-injury and against external stimuli that would aggravate overstimulation already present. Gastric
contents may be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully
titrated dosage of a short-acting barbiturate before performing gastric lavage. Other measures to
detoxify the gut include administration of activated charcoal and a cathartic.
Intensive care must be provided to maintain adequate circulation and respiratory exchange;
external cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not
been established.
HOW SUPPLIED
Tablets 5 mg - round, yellow (imprinted CIBA 7)
Bottles of 100……………………………………………………………......NDC
0078-0439-05
Tablets 10 mg - round, pale green, scored (imprinted CIBA 3)
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Bottles of 100……………………………………………………………......NDC
0078-0440-05
Tablets 20 mg - round, pale yellow, scored (imprinted CIBA 34)
Bottles of 100……………………………………………………………......NDC 0078-0441-
05
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from light.
Dispense in tight, light-resistant container (USP).
SR Tablets 20 mg - round, white, coated (imprinted CIBA 16)
Bottles of 100……………………………………………………………...NDC 0078-0442-05
Note: SR Tablets are color-additive free.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from moisture.
Dispense in tight, light-resistant container (USP).
T2006-56
REV: JUNE 2006
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
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T2006-62
Ritalin LA®
(methylphenidate hydrochloride)
extended-release capsules
Rx only
Prescribing Information
DESCRIPTION
Methylphenidate hydrochloride is a central nervous system (CNS) stimulant.
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is an
extended-release formulation of methylphenidate with a bi-modal release profile. Ritalin LA®
uses the proprietary SODAS® (Spheroidal Oral Drug Absorption System) technology. Each
bead-filled Ritalin LA capsule contains half the dose as immediate-release beads and half as
enteric-coated, delayed-release beads, thus providing an immediate release of
methylphenidate and a second delayed release of methylphenidate. Ritalin LA 10, 20, 30, and
40 mg capsules provide in a single dose the same amount of methylphenidate as dosages of 5,
10, 15, or 20 mg of Ritalin® tablets given b.i.d.
The active substance in Ritalin LA is methyl α-phenyl-2-piperidineacetate
hydrochloride, and its structural formula is
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its
solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol,
and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77.
Inactive ingredients: ammonio methacrylate copolymer, black iron oxide (10 and
40 mg capsules only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron
oxide (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide, triethyl citrate, and
yellow iron oxide (10, 30, and 40 mg capsules only).
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CLINICAL PHARMACOLOGY
Pharmacodynamics
Methylphenidate hydrochloride, the active ingredient in Ritalin LA® (methylphenidate
hydrochloride) extended-release capsules, is a central nervous system (CNS) stimulant. The
mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.
Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the
presynaptic neuron and increase the release of these monoamines into the extraneuronal
space. Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The
d-threo enantiomer is more pharmacologically active than the l-threo enantiomer.
Pharmacokinetics
Absorption
Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks
approximately four hours apart) when orally administered to children diagnosed with ADHD
and to healthy adults. The initial rate of absorption for Ritalin LA is similar to that of Ritalin
tablets as shown by the similar rate parameters between the two formulations, i.e., initial lag
time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached
in 1-3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak
(Tmax2) are also similar for Ritalin LA given once daily and Ritalin tablets given in two doses 4
hours apart (see Figure 1 and Table 1), although the ranges observed are greater for Ritalin
LA.
Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher
interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin
tablets given in two doses given 4 hours apart. This is due to an earlier onset and more
prolonged absorption from the delayed-release beads (see Figure 1 and Table 1).
The relative bioavailability of Ritalin LA given once daily is comparable to the same
total dose of Ritalin tablets given in two doses 4 hours apart in both children and in adults.
Figure 1. Mean plasma concentration time-profile of methylphenidate after a
single dose of Ritalin LA® 40 mg q.d. and Ritalin® 20 mg given in two doses
four hours apart
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Table 1. Mean ± SD and range of pharmacokinetic parameters of
methylphenidate after a single dose of Ritalin LA® and Ritalin® given in two
doses 4 hours apart
Population
Children
Adult Males
Formulation
Dose
Ritalin®
10 mg & 10 mg
Ritalin LA®
20 mg
Ritalin®
10 mg & 10 mg
Ritalin LA®
20 mg
N
21
18
9
8
Tlag (h)
0.24 ± 0.44
0.28 ± 0.46
1.0 ± 0.5
0.7 ± 0.2
0 - 1
0 - 1
0.7 - 1.3
0.3 - 1.0
Tmax1 (h)
1.8 ± 0.6
2.0 ± 0.8
1.9 ± 0.4
2.0 ± 0.9
1 - 3
1 - 3
1.3 - 2.7
1.3 - 4.0
Cmax1 (ng/mL)
10.2 ± 4.2
10.3 ± 5.1
4.3 ± 2.3
5.3 ± 0.9
4.2 - 20.2
5.5 - 26.6
1.8 - 7.5
3.8 - 6.9
Tminip (h)
4.0 ± 0.2
4.5 ± 1.2
3.8 ± 0.4
3.6 ± 0.6
4 - 5
2 - 6
3.3 - 4.3
2.7 - 4.3
Cminip (ng/mL)
5.8 ± 2.7
6.1 ± 4.1
1.2 ± 1.4
3.0 ± 0.8
3.1 - 14.4
2.9 - 21.0
0.0 - 3.7
1.7 - 4.0
Tmax2 (h)
5.6 ± 0.7
6.6 ± 1.5
5.9 ± 0.5
5.5 ± 0.8
5 - 8
5 - 11
5.0 - 6.5
4.3 - 6.5
Cmax2 (ng/mL)
15.3 ± 7.0
10.2 ± 5.9
5.3 ± 1.4
6.2 ± 1.6
6.2 - 32.8
4.5 - 31.1
3.6 - 7.2
3.9 - 8.3
AUC(0-∞)
102.4 ± 54.6
86.6 ± 64.0a
37.8 ± 21.9
45.8 ± 10.0
(ng/mL x h-1)
40.5 - 261.6
43.3 - 301.44
14.3 - 85.3
34.0 - 61.6
t1/2 (h)
2.5 ± 0.8
2.4 ± 0.7a
3.5 ± 1.9
3.3 ± 0.4
1.8 - 5.3
1.5 - 4.0
1.3 - 7.7
3.0 - 4.2
a N = 15
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Dose Proportionality
After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight
upward trend in the methylphenidate area under the curve (AUC) and peak plasma
concentrations (Cmax1 and Cmax2).
Distribution
Binding to plasma proteins is low (10%-33%), and the apparent distribution volume at steady
state with intravenous administration has been reported to be approximately 6 L/kg.
Metabolism
The absolute oral bioavailability of methylphenidate in children has been reported to be about
30% (range 10%-52%), suggesting pronounced presystemic metabolism. Biotransformation of
methylphenidate is rapid and extensive leading to the main, de-esterified metabolite α-phenyl-
2-piperidine acetic acid (ritalinic acid). Only small amounts of hydroxylated metabolites
(e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma.
Therapeutic activity is principally due to the parent compound.
Elimination
In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is
eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours).
In children the average half-life is about 2.5 hours, with a range of about 1.5 - 5.0 hours. The
rapid half-life in both children and adults may result in unmeasurable concentrations between
the morning and mid-day doses with Ritalin tablets. No accumulation of methylphenidate is
expected following multiple once a day oral dosing with Ritalin LA. The half-life of ritalinic
acid is about 3-4 hours.
After oral administration of an immediate release formulation of methylphenidate,
78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of
metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate
appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the
remainder being accounted for by minor metabolites.
Food Effects
Administration times relative to meals and meal composition may need to be individually
titrated.
When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had
a longer lag time until absorption began and variable delays in the time until the first peak
concentration, the time until the interpeak minimum, and the time until the second peak. The
first peak concentration and the extent of absorption were unchanged after food relative to the
fasting state, although the second peak was approximately 25% lower. The effect of a high fat
lunch was not examined.
There were no differences in the pharmacokinetics of Ritalin LA when administered
with applesauce, compared to administration in the fasting condition. There is no evidence of
dose dumping in the presence or absence of food.
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For patients unable to swallow the capsule, the contents may be sprinkled on
applesauce and administered (see DOSAGE AND ADMINISTRATION).
Special Populations
Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between
7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The
time until the between peak minimum, and the time until the second peak were delayed and
more variable in children compared to adults. After a 20-mg dose of Ritalin LA,
concentrations in children were approximately twice the concentrations observed in 18 to 35
year old adults. This higher exposure is almost completely due to the smaller body size and
total volume of distribution in children, as apparent clearance normalized to body weight is
independent of age.
Gender: There were no apparent gender differences in the pharmacokinetics of
methylphenidate between healthy male and female adults when administered Ritalin LA.
Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal
insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate
since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound,
and the major metabolite (ritalinic acid), has little or no pharmacologic activity.
Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency.
Hepatic insufficiency is expected to have minimal effect on the pharmacokinetics of
methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal
hydrolytic esterases that are widely distributed throughout the body.
CLINICAL STUDIES
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules was evaluated in a
randomized, double-blind, placebo-controlled, parallel group clinical study in which 134
children, ages 6 to 12, with DSM-IV diagnoses of Attention Deficit Hyperactivity Disorder
(ADHD) received a single morning dose of Ritalin LA in the range of 10-40 mg/day, or
placebo, for up to 2 weeks. The doses used were the optimal doses established in a previous
individual dose titration phase. In that titration phase, 53 of 164 patients (32%) started on a
daily dose of 10 mg and 111 of 164 patients (68%) started on a daily dose of 20 mg or higher.
The patient’s regular schoolteacher completed the Conners ADHD/DSM-IV Scale for
Teachers (CADS-T) at baseline and the end of each week. The CADS-T assesses symptoms
of hyperactivity and inattention. The change from baseline of the (CADS-T) scores during the
last week of treatment was analyzed as the primary efficacy parameter. Patients treated with
Ritalin LA showed a statistically significant improvement in symptom scores from baseline
over patients who received placebo. (See Figure 2.) This demonstrates that a single morning
dose of Ritalin LA exerts a treatment effect in ADHD.
Figure 2. CADS-T total subscale - Mean change from baseline*
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INDICATIONS AND USAGE
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is indicated for the
treatment of Attention Deficit Hyperactivity Disorder (ADHD).
The efficacy of Ritalin LA in the treatment of ADHD was established in one
controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL
PHARMACOLOGY).
A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies
the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and
were present before age 7 years. The symptoms must cause clinically significant impairment,
e.g., in social, academic, or occupational functioning, and be present in two or more settings,
e.g., school (or work) and at home. The symptoms must not be better accounted for by another
mental disorder. For the Inattentive Type, at least six of the following symptoms must have
persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained
attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks
requiring sustained mental effort; loses things; easily distracted; forgetful. For the
Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at
least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty
with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn;
intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to
be met.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test.
Adequate diagnosis requires the use not only of medical but of special psychological,
educational, and social resources. Learning may or may not be impaired. The diagnosis must
be based upon a complete history and evaluation of the child and not solely on the presence of
the required number of DSM-IV characteristics.
Need for Comprehensive Treatment Program
Ritalin LA is indicated as an integral part of a total treatment program for ADHD that may
include other measures (psychological, educational, social) for patients with this syndrome.
Drug treatment may not be indicated for all children with this syndrome. Stimulants are not
intended for use in the child who exhibits symptoms secondary to environmental factors
and/or other primary psychiatric disorders, including psychosis. Appropriate educational
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Page 7
placement is essential and psychosocial intervention is often helpful. When remedial measures
alone are insufficient, the decision to prescribe stimulant medication will depend upon the
physician’s assessment of the chronicity and severity of the child’s symptoms.
Long-Term Use
The effectiveness of Ritalin LA for long-term use, i.e., for more than 2 weeks, has not been
systematically evaluated in controlled trials. Therefore, the physician who elects to use Ritalin
LA for extended periods should periodically re-evaluate the long-term usefulness of the drug
for the individual patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Agitation
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is contraindicated in
marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.
Hypersensitivity to Methylphenidate
Ritalin LA is contraindicated in patients known to be hypersensitive to methylphenidate or
other components of the product.
Glaucoma
Ritalin LA is contraindicated in patients with glaucoma.
Tics
Ritalin LA is contraindicated in patients with motor tics or with a family history or diagnosis
of Tourette’s syndrome. (See ADVERSE REACTIONS.)
Monoamine Oxidase Inhibitors
Ritalin LA is contraindicated during treatment with monoamine oxidase inhibitors, and also
within a minimum of 14 days following discontinuation of treatment with a monoamine
oxidase inhibitor (hypertensive crises may result).
WARNINGS
Serious Cardiovascular Events
Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other
Serious Heart Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in
children and adolescents with structural cardiac abnormalities or other serious heart problems.
Although some serious heart problems alone carry an increased risk of sudden death,
stimulant products generally should not be used in children or adolescents with known serious
structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other
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Page 8
serious cardiac problems that may place them at increased vulnerability to the
sympathomimetic effects of a stimulant drug.
Adults
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant
drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also
unknown, adults have a greater likelihood than children of having serious structural cardiac
abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease,
or other serious cardiac problems. Adults with such abnormalities should also generally not be
treated with stimulant drugs.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg)
and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the
mean changes alone would not be expected to have short-term consequences, all patients
should be monitored for larger changes in heart rate and blood pressure. Caution is indicated
in treating patients whose underlying medical conditions might be compromised by increases
in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent
myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant
Medications
Children, adolescents, or adults who are being considered for treatment with stimulant
medications should have a careful history (including assessment for a family history of
sudden death or ventricular arrhythmia) and physical exam to assess for the presence of
cardiac disease, and should receive further cardiac evaluation if findings suggest such disease
(e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as
exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease
during stimulant treatment should undergo a prompt cardiac evaluation.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought
disorder in patients with a pre-existing psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid
bipolar disorder because of concern for possible induction of a mixed/manic episode in such
patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive
symptoms should be adequately screened to determine if they are at risk for bipolar disorder;
such screening should include a detailed psychiatric history, including a family history of
suicide, bipolar disorder, and depression.
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Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking,
or mania in children and adolescents without a prior history of psychotic illness or mania can
be caused by stimulants at usual doses. If such symptoms occur, consideration should be
given to a possible causal role of the stimulant, and discontinuation of treatment may be
appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such
symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to
methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated
patients compared to 0 in placebo-treated patients.
Aggression
Aggressive behavior or hostility is often observed in children and adolescents with ADHD,
and has been reported in clinical trials and the postmarketing experience of some medications
indicated for the treatment of ADHD. Although there is no systematic evidence that
stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD
should be monitored for the appearance of or worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to
either methylphenidate or non-medication treatment groups over 14 months, as well as in
naturalistic subgroups of newly methylphenidate-treated and non-medication treated children
over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children
(i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth
rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight
over 3 years), without evidence of growth rebound during this period of development. In the
double-blind placebo-controlled study of Ritalin LA® (methylphenidate hydrochloride)
extended-release capsules, the mean weight gain was greater for patients receiving placebo
(+1.0 kg) than for patients receiving Ritalin LA (+0.1 kg). Published data are inadequate to
determine whether chronic use of amphetamines may cause a similar suppression of growth,
however, it is anticipated that they likely have this effect as well. Therefore, growth should be
monitored during treatment with stimulants, and patients who are not growing or gaining
height or weight as expected may need to have their treatment interrupted.
Seizures
There is some clinical evidence that stimulants may lower the convulsive threshold in patients
with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures,
and, very rarely, in patients without a history of seizures and no prior EEG evidence of
seizures. In the presence of seizures, the drug should be discontinued.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant
treatment.
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Use in Children Under Six Years of Age
Ritalin LA should not be used in children under six years of age, since safety and efficacy in
this age group have not been established.
Drug Dependence
Ritalin LA should be given cautiously to patients with a history of drug dependence or
alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence
with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially
with parenteral abuse. Careful supervision is required during withdrawal from abusive use,
since severe depression may occur. Withdrawal following chronic therapeutic use may
unmask symptoms of the underlying disorder that may require follow-up.
PRECAUTIONS
Hematologic Monitoring
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Information for Patients
Patient information is provided at the end of this insert. To assure safe and effective use of
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the patient
information should be discussed with patients.
Drug Interactions
Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic
esterases) to ritalinic acid and not through oxidative pathways.
The effects of gastrointestinal pH alterations on the absorption of methylphenidate
from Ritalin LA have not been studied. Since the modified release characteristics of Ritalin
LA are pH dependent, the coadministration of antacids or acid suppressants could alter the
release of methylphenidate.
Methylphenidate may decrease the hypotensive effect of guanethidine. Because of
possible effects on blood pressure, methylphenidate should be used cautiously with pressor
agents.
Human pharmacologic studies have shown that methylphenidate may inhibit the
metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin,
primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward
dose adjustment of these drugs may be required when given concomitantly with
methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug
concentrations (or, in the case of coumarin, coagulation times), when initiating or
discontinuing concomitant methylphenidate.
Serious adverse events have been reported in concomitant use of methylphenidate with
clonidine, although no causality for the combination has been established. The safety of using
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methylphenidate in combination with clonidine or other centrally acting alpha-2-agonists has
not been systematically evaluated.
Carcinogenesis/Mutagenesis/Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an
increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a
daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times
the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively.
Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in
total malignant hepatic tumors. The mouse strain used is sensitive to the development of
hepatic tumors, and the significance of these results to humans is unknown.
Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity
study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which
is approximately 22 times and 5 times the maximum recommended human dose on a mg/kg
and mg/m2 basis, respectively.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is
sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and
female mice were fed diets containing the same concentration of methylphenidate as in the
lifetime carcinogenicity study; the high-dose groups were exposed to 60-74 mg/kg/day of
methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in
the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and
chromosome aberrations were increased, indicative of a weak clastogenic response, in an in
vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in
vivo in males and females in the mouse bone marrow micronucleus assay.
Methylphenidate did not impair fertility in male or female mice that were fed diets
containing the drug in an 18-week Continuous Breeding study. The study was conducted at
doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended dose
on a mg/kg and mg/m2 basis, respectively.
Pregnancy
Pregnancy Category C
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of
up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic
effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose,
which is approximately 40 times the maximum recommended human dose (MRHD) on a
mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day
(11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic
activity in rats, although increased incidences of fetal skeletal variations were seen at the
highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic.
The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the
MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout
pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was
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decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on
postnatal development were observed. The no effect level for pre- and postnatal development
in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis).
Adequate and well-controlled studies in pregnant women have not been conducted.
Ritalin LA should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Nursing Mothers
It is not known whether methylphenidate is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised if Ritalin LA is administered to a nursing
woman.
Pediatric Use
Long-term effects of methylphenidate in children have not been well established. Ritalin LA
should not be used in children under six years of age (see WARNINGS).
In a study conducted in young rats, methylphenidate was administered orally at doses
of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7)
and continuing through sexual maturity (Postnatal Week 10). When these animals were tested
as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in
males and females previously treated with 50 mg/kg/day (approximately 6 times the
maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in
the acquisition of a specific learning task was seen in females exposed to the highest dose
(12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral
development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical
significance of the long-term behavioral effects observed in rats is unknown.
ADVERSE REACTIONS
The clinical program for Ritalin LA® (methylphenidate hydrochloride) extended-release
capsules consisted of six studies: two controlled clinical studies conducted in children with
ADHD aged 6-12 years and four clinical pharmacology studies conducted in healthy adult
volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61
healthy adult volunteers. The subjects received Ritalin LA in doses of 10-40 mg per day.
Safety of Ritalin LA was assessed by evaluating frequency and nature of adverse events,
routine laboratory tests, vital signs, and body weight.
Adverse events during exposure were obtained primarily by general inquiry and
recorded by clinical investigators using terminology of their own choosing. Consequently, it
is not possible to provide a meaningful estimate of the proportion of individuals experiencing
adverse events without first grouping similar types of events into a smaller number of
standardized event categories. In the tables and listings that follow, MEDRA terminology has
been used to classify reported adverse events. The stated frequencies of adverse events
represent the proportion of individuals who experienced, at least once, a treatment-emergent
adverse event of the type listed. An event was considered treatment emergent if it occurred for
the first time or worsened while receiving therapy following baseline evaluation.
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Adverse Events in a Double-Blind, Placebo-Controlled Clinical Trial with
Ritalin LA
Treatment-Emergent Adverse Events
A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the
efficacy and safety of Ritalin LA in children with ADHD aged 6-12 years. All subjects
received Ritalin LA for up to 4 weeks, and had their dose optimally adjusted, prior to entering
the double-blind phase of the trial. In the two-week double-blind treatment phase of this
study, patients received either placebo or Ritalin LA at their individually-titrated dose (range
10 mg-40 mg).
The prescriber should be aware that these figures cannot be used to predict the
incidence of adverse events in the course of usual medical practice where patient
characteristics and other factors differ from those which prevailed in the clinical trials.
Similarly, the cited frequencies cannot be compared with figures obtained from other clinical
investigations involving different treatments, uses, and investigators. The cited figures,
however, do provide the prescribing physician with some basis for estimating the relative
contribution of drug and non-drug factors to the adverse event incidence rate in the population
studied.
Adverse events with an incidence >5% during the initial four-week single-blind
Ritalin LA titration period of this study were headache, insomnia, upper abdominal pain,
appetite decreased, and anorexia.
Treatment-emergent adverse events with an incidence >2% among Ritalin LA-treated
subjects, during the two-week double-blind phase of the clinical study, were as follows:
Preferred term
Ritalin LA®
N=65
N (%)
Placebo
N=71
N (%)
Anorexia
2 (3.1)
0 (0.0)
Insomnia
2 (3.1)
0 (0.0)
Adverse Events Associated with Discontinuation of Treatment
In the two-week double-blind treatment phase of a placebo-controlled parallel-group study in
children with ADHD, only one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an
adverse event (depression).
In the single-blind titration period of this study, subjects received Ritalin LA for up to
4 weeks. During this period a total of six subjects (6/161, 3.7%) discontinued due to adverse
events. The adverse events leading to discontinuation were anger (in 2 patients), hypomania,
anxiety, depressed mood, fatigue, migraine and lethargy.
Adverse Events with Other Methylphenidate HCl Dosage Forms
Nervousness and insomnia are the most common adverse reactions reported with other
methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during
prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of
the other adverse reactions listed below may also occur.
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Other reactions include:
Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia
Gastrointestinal: abdominal pain, nausea
Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia,
exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing
vasculitis, and thrombocytopenic purpura.
Metabolism/Nutrition: anorexia, weight loss during prolonged therapy
Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s
syndrome, toxic psychosis
Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion
Although a definite causal relationship has not been established, the following have
been reported in patients taking methylphenidate:
Blood/Lymphatic: leukopenia and/or anemia
Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma
Psychiatric: transient depressed mood, aggressive behavior
Skin/Subcutaneous: scalp hair loss
Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and,
in most of these, patients were concurrently receiving therapies associated with NMS. In a
single report, a ten-year-old boy who had been taking methylphenidate for approximately 18
months experienced an NMS-like event within 45 minutes of ingesting his first dose of
venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response
to either drug alone, or some other cause.
DRUG ABUSE AND DEPENDENCE
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, like other products
containing methylphenidate, is a Schedule II controlled substance. (See WARNINGS for
boxed warning containing drug abuse and dependence information.)
OVERDOSAGE
Signs and Symptoms
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the
central nervous system and from excessive sympathomimetic effects, may include the
following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be
followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing,
headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension,
mydriasis, and dryness of mucous membranes.
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Poison Control Center
Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance
and advice.
Recommended Treatment
As with the management of all overdosage, the possibility of multiple drug ingestion should
be considered.
When treating overdose, practitioners should bear in mind that there is a prolonged
release of methylphenidate from Ritalin LA® (methylphenidate hydrochloride) extended-
release capsules.
Treatment consists of appropriate supportive measures. The patient must be protected
against self-injury and against external stimuli that would aggravate overstimulation already
present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing
gastric lavage, control agitation and seizures if present and protect the airway. Other measures
to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care
must be provided to maintain adequate circulation and respiratory exchange; external cooling
procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate
overdosage has not been established; also, dialysis is considered unlikely to be of benefit due
to the large volume of distribution of methylphenidate.
DOSAGE AND ADMINISTRATION
Administration of Dose
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is for oral
administration once daily in the morning. Ritalin LA may be swallowed as whole capsules or
alternatively may be administered by sprinkling the capsule contents on a small amount of
applesauce (see specific instructions below). Ritalin LA and/or their contents should not be
crushed, chewed, or divided.
The capsules may be carefully opened and the beads sprinkled over a spoonful of
applesauce. The applesauce should not be warm because it could affect the modified release
properties of this formulation. The mixture of drug and applesauce should be consumed
immediately in its entirety. The drug and applesauce mixture should not be stored for future
use.
Dosing Recommendations
Dosage should be individualized according to the needs and responses of the patients.
Initial Treatment
The recommended starting dose of Ritalin LA is 20 mg once daily. Dosage may be adjusted in
weekly 10 mg increments to a maximum of 60 mg/day taken once daily in the morning,
depending on tolerability and degree of efficacy observed. Daily dosage above 60 mg is not
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Page 16
recommended. When in the judgement of the clinician a lower initial dose is appropriate,
patients may begin treatment with Ritalin LA 10 mg.
Patients Currently Receiving Methylphenidate
The recommended dose of Ritalin LA for patients currently taking methylphenidate b.i.d. or
sustained release (SR) is provided below.
Previous Methylphenidate Dose
Recommended Ritalin LA® Dose
5 mg methylphenidate-b.i.d.
10 mg q.d.
10 mg methylphenidate b.i.d.
or 20 mg methylphenidate-SR
20 mg q.d.
15 mg methylphenidate b.i.d.
30 mg q.d.
20 mg methylphenidate b.i.d.
or 40 mg of methylphenidate-SR
40 mg q.d.
30 mg methylphenidate b.i.d.
or 60 mg methylphenidate-SR
60 mg q.d.
For other methylphenidate regimens, clinical judgment should be used when selecting
the starting dose. Ritalin LA dosage may be adjusted at weekly intervals in 10 mg increments.
Daily dosage above 60 mg is not recommended.
Maintenance/Extended Treatment
There is no body of evidence available from controlled trials to indicate how long the patient
with ADHD should be treated with Ritalin LA. It is generally agreed, however, that
pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the
physician who elects to use Ritalin LA for extended periods in patients with ADHD should
periodically re-evaluate the long-term usefulness of the drug for the individual patient with
trials off medication to assess the patient’s functioning without pharmacotherapy.
Improvement may be sustained when the drug is either temporarily or permanently
discontinued.
Dose Reduction and Discontinuation
If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be
reduced, or, if necessary, the drug should be discontinued. If improvement is not observed
after appropriate dosage adjustment over a one-month period, the drug should be
discontinued.
HOW SUPPLIED
Ritalin LA capsules 10 mg: white/light brown (imprinted NVR R10)
Bottles of 100………………………………………………………NDC 0078-0424-05
Ritalin LA capsules 20 mg: white (imprinted NVR R20)
Bottles of 100………………………………………………………NDC 0078-0370-05
Ritalin LA capsules 30 mg: yellow (imprinted NVR R30)
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Bottles of 100………………………………………………………NDC 0078-0371-05
Ritalin LA capsules 40 mg: light brown (imprinted NVR R40)
Bottles of 100………………………………………………………NDC 0078-0372-05
Store at 25°C (77°F), excursions permitted 15°C-30°C (59°F-86°F). [See USP controlled
room temperature]
Dispense in tight container (USP).
Ritalin LA® is a trademark of Novartis AG.
SODAS® is a trademark of Elan Corporation, plc.
This product is covered by US patents including US 5,837,284 and 6,228,398.
REFERENCE
American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders.
4th edition. Washington DC: American Psychiatric Association 1994.
REV: JUNE 2006
T2006-62
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Page 18
INFORMATION FOR PATIENTS TAKING RITALIN LA®, OR FOR
THEIR PARENTS OR CAREGIVERS
Once Daily
Ritalin LA®
(methylphenidate hydrochloride)
extended-release capsules
This information for patients or their parents or caregivers is about Ritalin LA. Please read
this before you start taking Ritalin LA. Also, read the information you get each time you
renew your prescription, in case anything has changed. Remember, this information does not
take the place of your doctor’s instructions. If you have any questions about this information
or about Ritalin LA, talk to your doctor or pharmacist.
WHAT IS RITALIN LA?
Ritalin LA is a once-a-day treatment for Attention Deficit Hyperactivity Disorder, or ADHD.
Ritalin LA contains the drug methylphenidate (Ritalin®), a central nervous system stimulant
that has been used to treat ADHD for more than 30 years. Ritalin is available in several forms
including Ritalin LA, an extended-release form of methylphenidate hydrochloride available as
10, 20, 30, and 40 mg extended-release capsules. Ritalin LA is taken by mouth, once each day
in the morning, before breakfast.
WHAT IS ATTENTION DEFICIT HYPERACTIVITY DISORDER?
ADHD has three main types of symptoms: inattention, hyperactivity, and impulsiveness.
Symptoms of inattention include not paying attention, making careless mistakes, not listening,
not finishing tasks, not following directions, and being easily distracted. Symptoms of
hyperactivity and impulsiveness include fidgeting, talking excessively, running around at
inappropriate times, and interrupting others. Some patients have more symptoms of
hyperactivity and impulsiveness while others have more symptoms of inattentiveness. Some
patients have all three types of symptoms.
Many people have symptoms like these from time to time, but patients with ADHD
have these symptoms more than others their age. Symptoms must be present for at least 6
months to be certain of the diagnosis.
HOW DOES RITALIN LA WORK?
When you take a Ritalin LA capsule, half of the beads provide an immediate dose of
methylphenidate and the other half provide a delayed second release of the drug to continue to
help lessen the symptoms of ADHD during the day. Methylphenidate, the active ingredient in
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Ritalin LA, helps increase attention and decrease impulsiveness and hyperactivity in patients
with ADHD.
BEFORE RITALIN LA TREATMENT
It is very important that ADHD be accurately diagnosed and that the need for medication be
carefully assessed. It is important to remember that Ritalin is only part of the overall
management of ADHD. Parents, teachers, physicians and other professionals are part of a
team that must work together.
Before Ritalin treatment, your doctor should be made aware of any current or past
physical or mental problems. Tell your doctor if there is a history of drug or alcohol abuse,
depression, bipolar disorder, psychosis, epilepsy or seizure disorders, high blood pressure,
heart defects, irregular heart rhythms, other heart problems, glaucoma, and facial tics
(involuntary movements). Also tell your doctor if there is a family history of sudden death,
irregular heart rhythm, suicide, bipolar disorder, depression or Tourette’s syndrome.
Both your doctor and your pharmacist should also be informed of all medicines that
you are taking, even if these drugs are not taken on a regular basis and are available without
prescription. Your doctor will decide whether you can take Ritalin with other medicines.
Methylphenidate is known to interact with a number of other drugs. These include medicines
to treat depression, such as monoamine oxidase inhibitors; to control seizures; and to thin
blood. Sometimes these interactions may require a change in dosage, or occasionally stopping
one of the drugs involved.
Tell your doctor if you are pregnant or nursing a baby.
WHO SHOULD NOT TAKE RITALIN LA ?
You should NOT take Ritalin LA if:
• You have known serious heart defects, serious heart rhythm irregularities, or other serious
heart problems.
• You have significant anxiety, tension, or agitation since Ritalin LA may make these
conditions worse.
• You are allergic to methylphenidate or any of the other ingredients in Ritalin LA.
• You have glaucoma, an eye disease.
• You have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome.
• You are taking a monoamine oxidase inhibitor, a type of drug, or have discontinued a
monoamine oxidase inhibitor in the last 14 days.
Talk to your doctor if you believe any of these conditions apply to you.
HOW SHOULD I TAKE RITALIN LA ?
Take Ritalin LA once each day in the morning.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 20
Take the dose prescribed by your doctor. Your doctor may adjust the amount of drug
you take until it is right for you. From time to time, your doctor may interrupt your treatment
to check your symptoms while you are not taking the drug.
Ritalin LA capsules may be taken at the same time as food or without food, although
food may delay the absorption of Ritalin LA. The Ritalin LA capsule may be swallowed as
whole capsules or the capsule may be opened and sprinkled on a small amount of applesauce.
The capsule should not be crushed or chewed or its contents divided.
To sprinkle the contents of the capsule, open the capsule carefully and sprinkle the
beads over a spoonful of applesauce. The applesauce should not be warm because it could
affect the modified release properties of this formulation. The mixture of drug and applesauce
should be consumed immediately in its entirety. The drug and applesauce mixture should not
be stored for future use.
If you also take antiacids or drugs that suppress stomach acids, you should discuss
with your physician or pharmacist how to take these drugs with Ritalin LA.
WHAT ARE THE POSSIBLE SIDE EFFECTS OF RITALIN LA?
The most common side effects of Ritalin LA are:
• Nervousness
• Stomach pain
• Sleeplessness
• Decreased appetite
Other side effects seen with methylphenidate, the active ingredient in Ritalin LA,
include nausea, vomiting, dizziness, tics, allergic reactions, increased blood pressure and
psychosis (abnormal thinking or hallucinations).
Dependence
Abuse of methylphenidate can lead to dependence. Tell your doctor if you have ever abused
or been dependent on alcohol or drugs, or if you are now abusing or dependent on alcohol or
drugs. Misuse of stimulants may be associated with sudden death and serious cardiovascular
adverse events.
Blurred Vision
Tell your doctor if you have blurred vision when taking Ritalin LA. This could be a sign of a
serious problem.
Slower Growth
Slower growth (weight gain and/or height) has been reported with long-term use of
methylphenidate in children. Your doctor will be carefully watching your height and weight.
If you are not growing or gaining weight as your doctor expects, your doctor may stop your
Ritalin LA treatment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 21
This is not a complete list of possible side effects. Ask your doctor about other side
effects. If you develop any side effect, talk to your doctor.
WHAT MUST I DISCUSS WITH MY DOCTOR BEFORE TAKING
RITALIN LA?
Talk to your doctor before taking RITALIN LA if you:
• Have high blood pressure.
• Have an abnormal heart rate or rhythm.
• Have had any other current or previous heart problems.
• Have a family history of sudden death or heart rhythm problems.
• Are being treated for depression or bipolar disorder, or have symptoms of depression such
as feelings of sadness, worthlessness, and hopelessness.
• Have a family history of suicide, bipolar disorder or depression.
• Have motion tics (hard-to-control, repeated twitching of any parts of your body) or verbal
tics (hard-to-control repeating of sounds or words).
• Have someone in your family with motion tics, verbal tics, or Tourette’s syndrome.
• Have abnormal thoughts or visions, hear abnormal sounds, or have been diagnosed with
psychosis.
• Have had seizures (convulsions, epilepsy) or abnormal EEGs (electroencephalograms).
Tell your doctor immediately if you develop any of the above conditions or symptoms while
taking Ritalin LA.
CAN I TAKE RITALIN LA WITH OTHER MEDICINES?
Tell your doctor about all medicines that you are taking or intend to take. Your doctor should
decide whether you can take Ritalin LA with other medicines. These include:
• Other medicines that a doctor has prescribed.
• All medicines that you buy yourself without a prescription.
• Any herbal remedies that you may be taking.
Monoamine Oxidase (MAO) Inhibitors
You should not take Ritalin LA with (MAO) inhibitors or within 14 days of stopping a MAO
inhibitor.
Starting a New Medicine
While on Ritalin LA, do not start taking a new medicine or herbal remedy before checking
with your doctor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 22
Other Medicines You May Be Taking
Ritalin LA may change the way your body reacts to certain medicines. These include
medicines used to treat depression, prevent seizures, or prevent blood clots (commonly called
“blood thinners”). Your doctor may need to change your dose of these medicines if you are
taking them with Ritalin LA.
Other Important Safety Information
Pregnancy and Nursing
Before taking Ritalin LA, tell your doctor if you are pregnant or plan on becoming pregnant.
If you take methylphenidate, it may be in your breast milk. Tell your doctor if you are nursing
a baby.
Overdose
Call your doctor immediately if you take more than the amount of Ritalin LA prescribed by
your doctor.
WHAT ELSE SHOULD I KNOW ABOUT RITALIN LA ?
Ritalin LA has not been studied in children under 6 years of age.
Ritalin LA may be a part of your overall treatment for ADHD. Your doctor may also
recommend that you have counseling or other therapy.
As with all medicines, never share Ritalin LA with anyone else and take only the
number of Ritalin LA capsules prescribed by your doctor.
Ritalin LA should be stored in a safe place at room temperature (between 59°F-86°F).
Do not store this medicine in hot, damp, or humid places. Keep the container of Ritalin LA in
a safe place, away from high-traffic areas where other people could have accidental or
unauthorized access to the medication. Keep track of the number of capsules so that you will
know if any are missing. Someone who has easy access to Ritalin may be able to give the
capsules to others or misuse the medication.
Keep out of the reach of children.
This leaflet summarizes the most important information about Ritalin LA. If you would like
more information, talk with your doctor. You can ask your pharmacist or doctor for
information about Ritalin LA that is written for health professionals.
You can also call 1-888 NOWNOVA (1-888-669-6682).
REV: JUNE 2006
T2006-63
REV: JUNE 2006
PRINTED IN U.S.A.
T2006-62/ T2006-63
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 23
Manufactured for
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
By ELAN HOLDINGS INC.
Pharmaceutical Division
Gainesville, GA 30504
©Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:29.625774
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/010187s66s67,018029s37s38,021284s6s8lbl.pdf', 'application_number': 18029, 'submission_type': 'SUPPL ', 'submission_number': 38}
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Novartis logo
Ritalin® hydrochloride
methylphenidate hydrochloride
tablets USP
Ritalin-SR®
methylphenidate hydrochloride USP
sustained-release tablets
Rx only
Prescribing Information
DESCRIPTION
Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS)
stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as
sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl
α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is chemical structure
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to
litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform
and in acetone. Its molecular weight is 269.77.
Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3
(10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets),
sucrose, talc, and tragacanth (20-mg tablets).
Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil,
povidone, titanium dioxide, and zein.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Ritalin is a mild central nervous system stimulant.
The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem
arousal system and cortex to produce its stimulant effect.
There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its
mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to
the condition of the central nervous system.
Reference ID: 2872329
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Effects on QT Interval
The effect of Focalin® XR (dexmethylphenidate, the pharmacologically active d-enantiomer of Ritalin)
on the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)
controlled study following single doses of Focalin® XR 40mg in 75 healthy volunteers. ECGs were
collected up to 12 h post-dose. Frederica’s method for heart rate correction was employed to derive the
corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and the
upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus
placebo. This was below the threshold of clinical concern and there was no evident-exposure response
relationship.
Pharmacokinetics
Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative
bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of
Ritalin major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and
101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR
tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in
children as compared to 86% in adults.
In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s
major metabolite appeared to be greater in females than in males. No gender differences were observed
for Ritalin plasma concentration in the same subjects.
INDICATIONS
Attention Deficit Disorders, Narcolepsy
Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms
being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal
Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction.
Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial
measures (psychological, educational, social) for a stabilizing effect in children with a behavioral
syndrome characterized by the following group of developmentally inappropriate symptoms:
moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity.
The diagnosis of this syndrome should not be made with finality when these symptoms are only of
comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal
EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not
be warranted.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis
requires the use not only of medical but of special psychological, educational, and social resources.
Characteristics commonly reported include: chronic history of short attention span, distractibility,
emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and
abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete
history and evaluation of the child and not solely on the presence of one or more of these characteristics.
Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in
the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric
disorders, including psychosis. Appropriate educational placement is essential and psychosocial
Reference ID: 2872329
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For current labeling information, please visit https://www.fda.gov/drugsatfda
intervention is generally necessary. When remedial measures alone are insufficient, the decision to
prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity
of the child’s symptoms.
CONTRAINDICATIONS
Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these
symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients
with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s
syndrome.
Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within a
minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises
may result).
WARNINGS
Serious Cardiovascular Events
Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart
Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children
and adolescents with structural cardiac abnormalities or other serious heart problems. Although some
serious heart problems alone carry an increased risk of sudden death, stimulant products generally should
not be used in children or adolescents with known serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place
them at increased vulnerability to the sympathomimetic effects of a stimulant drug.
Adults
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at
usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a
greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy,
serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults
with such abnormalities should also generally not be treated with stimulant drugs.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average
heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone
would not be expected to have short-term consequences, all patients should be monitored for larger
changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying
medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with
pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
Children, adolescents, or adults who are being considered for treatment with stimulant medications should
have a careful history (including assessment for a family history of sudden death or ventricular
arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further
cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients
Reference ID: 2872329
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For current labeling information, please visit https://www.fda.gov/drugsatfda
who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms
suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in
patients with a pre-existing psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar
disorder because of concern for possible induction of a mixed/ manic episode in such patients. Prior to
initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a detailed
psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in
children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants
at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the
stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-
term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of
3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated
patients compared to 0 in placebo-treated patients.
Aggression
Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been
reported in clinical trials and the postmarketing experience of some medications indicated for the
treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior
or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or
worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either
methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups
of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10
to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout
the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height
and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of
development. Published data are inadequate to determine whether chronic use of amphetamines may
cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well.
Therefore, growth should be monitored during treatment with stimulants, and patients who are not
growing or gaining height or weight as expected may need to have their treatment interrupted.
Seizures
There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior
history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in
patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures,
the drug should be discontinued.
Reference ID: 2872329
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Use in Children Under Six Years of Age
Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not
been established.
Drug Dependence
Ritalin should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic
abusive use can lead to marked tolerance and psychological dependence with varying degrees of
abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful
supervision is required during withdrawal from abusive use, since severe depression may occur.
Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may
require follow-up.
PRECAUTIONS
Patients with an element of agitation may react adversely; discontinue therapy if necessary.
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in
light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend
on the physician’s assessment of the chronicity and severity of the child’s symptoms and their
appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of
the behavioral characteristics.
When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not
indicated.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about
the benefits and risks associated with treatment with methylphenidate and should counsel them in its
appropriate use. A patient Medication Guide is available for Ritalin and Ritalin-SR. The prescriber or
health professional should instruct patients, their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The
complete text of the Medication Guide is reprinted at the end of this document.
Drug Interactions
Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with
MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible
effects on blood pressure, Ritalin should be used cautiously with pressor agents.
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is
metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways.
Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of
coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs
(e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be
required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and
Reference ID: 2872329
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For current labeling information, please visit https://www.fda.gov/drugsatfda
monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or
discontinuing methylphenidate.
Carcinogenesis/Mutagenesis/Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in
hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of
approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum
recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare
rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain
used is sensitive to the development of hepatic tumors, and the significance of these results to humans is
unknown.
Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in
F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5
times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic
carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing
the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups
were exposed to 60-74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse
lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were
increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster
Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone
marrow micronucleus assay.
Methlyphenidate did not impair fertility in male or female mice that were fed diets containing the drug in
an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day,
approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis,
respectively.
PREGNANCY
Pregnancy Category C
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and
200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence
of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the
maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal
development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence
of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen
at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no
effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2
basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up
to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a
mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre-
and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis).
Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Reference ID: 2872329
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Nursing Mothers
It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised if Ritalin is administered to a nursing woman.
Pediatric Use
Ritalin should not be used in children under six years of age (see WARNINGS).
In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100
mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through
sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14),
decreased spontaneous locomotor activity was observed in males and females previously treated with 50
mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis)
or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the
highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral
development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the
long-term behavioral effects observed in rats is unknown.
ADVERSE REACTIONS
Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing
dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity
(including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with
histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea;
dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and
down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy.
There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a
definite causal relationship has not been established, the following have been reported in patients taking
this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma;
isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood;
aggressive behavior; a few instances of scalp hair loss. Very rare reports of neuroleptic malignant
syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving
therapies associated with NMS. In a single report, a ten-year-old boy who had been taking
methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of
ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug
interaction, a response to either drug alone, or some other cause.
In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and
tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also
occur.
DOSAGE AND ADMINISTRATION
Dosage should be individualized according to the needs and responses of the patient.
Adults
Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals.
Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg
daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take
the last dose before 6 p.m.
Reference ID: 2872329
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR
tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the
titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or
chewed.
Children (6 years and over)
Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is
not recommended.
If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug
should be discontinued.
Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg
weekly.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR
tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the
titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or
chewed.
If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary,
discontinue the drug.
Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained
when the drug is either temporarily or permanently discontinued.
Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.
OVERDOSAGE
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central
nervous system and from excessive sympathomimetic effects, may include the following: vomiting,
agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria,
confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations,
cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.
Treatment consists of appropriate supportive measures. The patient must be protected against self-injury
and against external stimuli that would aggravate overstimulation already present. Gastric contents may
be evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a
short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include
administration of activated charcoal and a cathartic.
Intensive care must be provided to maintain adequate circulation and respiratory exchange; external
cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been
established.
HOW SUPPLIED
Tablets 5 mg - round, yellow (imprinted CIBA 7)
Bottles of 100 ...............................................……………………………......NDC 0078-0439-05
Tablets 10 mg - round, pale green, scored (imprinted CIBA 3)
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Bottles of 100 .................................................................................................NDC 0078-0440-05
Tablets 20 mg - round, pale yellow, scored (imprinted CIBA 34)
Bottles of 100 .......………………………………………………………......NDC 0078-0441-05
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from light.
Dispense in tight, light-resistant container (USP).
SR Tablets 20 mg - round, white, coated (imprinted CIBA 16)
Bottles of 100……………………………………………………………...NDC 0078-0442-05
Note: SR Tablets are color-additive free.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from moisture.
Dispense in tight, light-resistant container (USP).
MEDICATION GUIDE
RITALIN®
(methylphenidate hydrochloride tablets, USP) CII
Read the Medication Guide that comes with RITALIN® before you or your child starts taking it and each time you
get a refill. There may be new information. This Medication Guide does not take the place of talking to your
doctor about your or your child’s treatment with RITALIN®.
What is the most important information I should know about RITALIN®?
The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines.
1. Heart-related problems:
• sudden death in patients who have heart problems or heart defects
• stroke and heart attack in adults
• increased blood pressure and heart rate
Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family
history of these problems.
Your doctor should check you or your child carefully for heart problems before starting RITALIN® .
Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with
RITALIN® .
Call your doctor right away if you or your child has any signs of heart problems such as chest pain,
shortness of breath, or fainting while taking RITALIN®.
2. Mental (Psychiatric) problems:
All Patients
• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility
Children and Teenagers
• new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or
new manic symptoms
Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems
while taking RITALIN®, especially seeing or hearing things that are not real, believing things that are not
real, or are suspicious.
What Is RITALIN®?
RITALIN® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-
Deficit Hyperactivity Disorder (ADHD). RITALIN® may help increase attention and decrease impulsiveness and
hyperactivity in patients with ADHD.
RITALIN® should be used as a part of a total treatment program for ADHD that may include counseling or other
therapies.
RITALIN® is also used in the treatment of a sleep disorder called narcolepsy.
RITALIN® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep
RITALIN® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN® may harm others,
and is against the law.
Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol,
prescription medicines or street drugs.
Who should not take RITALIN®?
RITALIN® should not be taken if you or your child:
• are very anxious, tense, or agitated
• have an eye problem called glaucoma
• have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated
movements or sounds.
• are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase
inhibitor or MAOI.
• are allergic to anything in RITALIN®. See the end of this Medication Guide for a complete list of ingredients.
RITALIN® should not be used in children less than 6 years old because it has not been studied in this age group.
RITALIN® may not be right for you or your child. Before starting RITALIN® tell your or your child’s
doctor about all health conditions (or a family history of) including:
• heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar illness, or depression
• tics or Tourette’s syndrome
• seizures or have had an abnormal brain wave test (EEG)
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding.
Can RITALIN® be taken with other medicines?
Tell your doctor about all of the medicines that you or your child take including prescription and
nonprescription medicines, vitamins, and herbal supplements. RITALIN® and some medicines may interact
with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted
while taking RITALIN® .
Your doctor will decide whether RITALIN® can be taken with other medicines.
Especially tell your doctor if you or your child takes:
• anti-depression medicines including MAOIs
• seizure medicines
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• blood thinner medicines
• blood pressure medicines
• cold or allergy medicines that contain decongestants
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and
pharmacist.
Do not start any new medicine while taking RITALIN® without talking to your doctor first.
How should RITALIN® be taken?
• Take RITALIN® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your
child.
• Ritalin is usually taken 2 to 3 times a day.
• Take RITALIN® 30 to 45 minutes before a meal.
• From time to time, your doctor may stop RITALIN® treatment for a while to check ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN® . Children
should have their height and weight checked often while taking RITALIN® . RITALIN® treatment may be
stopped if a problem is found during these check-ups.
• If you or your child takes too much RITALIN® or overdoses, call your doctor or poison control center
right away, or get emergency treatment.
What are possible side effects of RITALIN®?
See “What is the most important information I should know about RITALIN®?” for information on reported
heart and mental problems.
Other serious side effects include:
• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision
Common side effects include:
• headache
• decreased appetite
• stomach ache
• nervousness
• trouble sleeping
• nausea
Talk to your doctor if you or your child has side effects that are bothersome or do not go away.
This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.
How should I store RITALIN®?
• Store RITALIN in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from light.
• Keep RITALIN® and all medicines out of the reach of children.
General information about RITALIN®
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
RITALIN® for a condition for which it was not prescribed. Do not give RITALIN® to other people, even if they
have the same condition. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about RITALIN®. If you would like more
information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN® that
was written for healthcare professionals. For more information about RITALIN® call 1-888-669-6682.
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the ingredients in RITALIN®?
Active Ingredient: methylphenidate HCL
Inactive Ingredients: D&C Yellow No.10 (5-mg and 20-mg tablets), FD&C Green No.3 (10-mg tablets), lactose,
magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg
tablets).
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
MEDICATION GUIDE
RITALIN-SR®
(methylphenidate hydrochloride, USP) sustained-release tablets CII
Read the Medication Guide that comes with RITALIN-SR® before you or your child starts taking it and each time
you get a refill. There may be new information. This Medication Guide does not take the place of talking to your
doctor about your or your child’s treatment with RITALIN-SR® .
What is the most important information I should know about RITALIN-SR®?
The following have been reported with use of methylphenidate hydrochloride and other stimulant
medicines.
1. Heart-related problems:
• sudden death in patients who have heart problems or heart defects
• stroke and heart attack in adults
• increased blood pressure and heart rate
Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family
history of these problems.
Your doctor should check you or your child carefully for heart problems before starting RITALIN-SR® .
Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with
RITALIN-SR® .
Call your doctor right away if you or your child has any signs of heart problems such as chest pain,
shortness of breath, or fainting while taking RITALIN-SR®.
2. Mental (Psychiatric) problems:
All Patients
• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility
Children and Teenagers
• new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or
new manic symptoms
Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar
illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems
while taking RITALIN-SR®, especially seeing or hearing things that are not real, believing things that are
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
not real, or are suspicious.
What Is RITALIN-SR®?
RITALIN-SR® is a central nervous system stimulant prescription medicine. It is used for the treatment of
Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN-SR® may help increase attention and decrease
impulsiveness and hyperactivity in patients with ADHD.
RITALIN-SR® should be used as a part of a total treatment program for ADHD that may include counseling or
other therapies.
RITALIN-SR® is also used in the treatment of a sleep disorder called narcolepsy.
RITALIN-SR® is a federally controlled substance (CII) because it can be abused or lead to dependence.
Keep RITALIN-SR® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN-SR® may
harm others, and is against the law.
Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol,
prescription medicines or street drugs.
Who should not take RITALIN-SR®?
RITALIN-SR® should not be taken if you or your child:
• are very anxious, tense, or agitated
• have an eye problem called glaucoma
• have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated
movements or sounds.
• are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase
inhibitor or MAOI.
• are allergic to anything in RITALIN-SR®. See the end of this Medication Guide for a complete list of
ingredients.
RITALIN-SR® should not be used in children less than 6 years old because it has not been studied in this age
group.
RITALIN-SR® may not be right for you or your child. Before starting RITALIN-SR® tell your or your
child’s doctor about all health conditions (or a family history of) including:
• heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar illness, or depression
• tics or Tourette’s syndrome
• seizures or have had an abnormal brain wave test (EEG)
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding.
Can RITALIN-SR® be taken with other medicines?
Tell your doctor about all of the medicines that you or your child take including prescription and
nonprescription medicines, vitamins, and herbal supplements. RITALIN-SR® and some medicines may
interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be
adjusted while taking RITALIN-SR®.
Your doctor will decide whether RITALIN-SR® can be taken with other medicines.
Especially tell your doctor if you or your child takes:
• anti-depression medicines including MAOIs
• seizure medicines
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• blood thinner medicines
• blood pressure medicines
• cold or allergy medicines that contain decongestants
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and
pharmacist.
Do not start any new medicine while taking RITALIN-SR® without talking to your doctor first.
How should RITALIN-SR® be taken?
• Take RITALIN-SR® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your
child.
• Take RITALIN-SR® 30 to 45 minutes before a meal. The effect of a dose of RITALIN-SR usually lasts about
8 hours.
• Do not chew or crush RITALIN-SR® tablets. Swallow RITALIN-SR® tablets whole with water or other
liquids. Tell your doctor if you or your child cannot swallow RITALIN-SR® whole. A different medicine may
need to be prescribed.
• From time to time, your doctor may stop RITALIN-SR® treatment for a while to check ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN-SR®.
Children should have their height and weight checked often while taking RITALIN-SR®. RITALIN-SR®
treatment may be stopped if a problem is found during these check-ups.
• If you or your child takes too much RITALIN-SR® or overdoses, call your doctor or poison control
center right away, or get emergency treatment.
What are possible side effects of RITALIN-SR®?
See “What is the most important information I should know about RITALIN-SR®?” for information on
reported heart and mental problems.
Other serious side effects include:
• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision
Common side effects include:
• headache
• decreased appetite
• stomach ache
• nervousness
• trouble sleeping
• nausea
Talk to your doctor if you or your child has side effects that are bothersome or do not go away.
This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.
How should I store RITALIN-SR®?
• Store RITALIN-SR® in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from moisture.
• Keep RITALIN-SR® and all medicines out of the reach of children.
General information about RITALIN-SR®
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
RITALIN-SR® for a condition for which it was not prescribed. Do not give RITALIN-SR® to other people, even if
they have the same condition. It may harm them and it is against the law.
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This Medication Guide summarizes the most important information about RITALIN-SR®. If you would like more
information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN-SR®
that was written for healthcare professionals. For more information about RITALIN-SR call 1-888-669-6682.
What are the ingredients in RITALIN-SR®?
Active Ingredient: methylphenidate HCL, USP
Inactive Ingredients: cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil,
povidone, titanium dioxide, and zein
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
REV: Month Year
T201X-XX/T2009-57/T2009-58
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINCIPAL DISPLAY PANEL
Package Label – 5 mg
Rx Only
NDC 0078-0439-05
Ritalin® HCL
Methylphenidate HCL USP
5 mg
100 Tablets
Dispense with Medication Guide attached or provided separately.
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINCIPAL DISPLAY PANEL
Package Label – 10 mg
Rx Only
NDC 0078-0440-05
Ritalin® HCL
Methylphenidate HCL USP
10 mg
100 Tablets
Dispense with Medication Guide attached or provided separately.
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINCIPAL DISPLAY PANEL
Package Label – 20 mg
Rx Only
NDC 0078-0441-05
Ritalin® HCL
Methylphenidate HCL USP
20 mg
100 Tablets
Dispense with Medication Guide attached or provided separately.
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINCIPAL DISPLAY PANEL
Package Label – 20 mg sustained-release
Rx Only
NDC 0078-0442-05
Ritalin-SR®
Methylphenidate HCL USP
sustained-release tablets
20 mg
100 Tablets
Dispense with Medication Guide attached or provided separately.
Reference ID: 2872329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:30.007398
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018029s043lbl.pdf', 'application_number': 18029, 'submission_type': 'SUPPL ', 'submission_number': 43}
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company logo
Ritalin® hydrochloride
methylphenidate hydrochloride
tablets USP
Ritalin-SR® company logo
methylphenidate hydrochloride USP
sustained-release tablets company logo
Rx only
Prescribing Information
DESCRIPTION
Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS)
stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as
sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl
α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is structural formula
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to
litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform
and in acetone. Its molecular weight is 269.77.
Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3
(10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets),
sucrose, talc, and tragacanth (20-mg tablets).
Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil,
povidone, titanium dioxide, and zein.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Ritalin is a mild central nervous system stimulant.
The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem
arousal system and cortex to produce its stimulant effect.
There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its
mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to
the condition of the central nervous system.
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Effects on QT Interval
The effect of Focalin® XR (dexmethylphenidate, the pharmacologically active d-enantiomer of Ritalin)
on the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)
controlled study following single doses of Focalin® XR 40mg in 75 healthy volunteers. ECGs were
collected up to 12 h post-dose. Frederica’s method for heart rate correction was employed to derive the
corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and the
upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus
placebo. This was below the threshold of clinical concern and there was no evident-exposure response
relationship.
Pharmacokinetics
Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative
bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of Ritalin
major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101%
(85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR tablets
and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in
children as compared to 86% in adults.
In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s
major metabolite appeared to be greater in females than in males. No gender differences were observed for
Ritalin plasma concentration in the same subjects.
INDICATIONS
Attention Deficit Disorders, Narcolepsy
Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms
being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal
Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction.
Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial
measures (psychological, educational, social) for a stabilizing effect in children with a behavioral
syndrome characterized by the following group of developmentally inappropriate symptoms:
moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity.
The diagnosis of this syndrome should not be made with finality when these symptoms are only of
comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal
EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be
warranted.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis
requires the use not only of medical but of special psychological, educational, and social resources.
Characteristics commonly reported include: chronic history of short attention span, distractibility,
emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and
abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete
history and evaluation of the child and not solely on the presence of one or more of these characteristics.
Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in
the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders,
including psychosis. Appropriate educational placement is essential and psychosocial intervention is
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant
medication will depend upon the physician’s assessment of the chronicity and severity of the child’s
symptoms.
CONTRAINDICATIONS
Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these
symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients
with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s
syndrome.
Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within a
minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises
may result).
WARNINGS
Serious Cardiovascular Events
Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart
Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children
and adolescents with structural cardiac abnormalities or other serious heart problems. Although some
serious heart problems alone carry an increased risk of sudden death, stimulant products generally should
not be used in children or adolescents with known serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place
them at increased vulnerability to the sympathomimetic effects of a stimulant drug.
Adults
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at
usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a
greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy,
serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with
such abnormalities should also generally not be treated with stimulant drugs.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average
heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone
would not be expected to have short-term consequences, all patients should be monitored for larger
changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying
medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with
pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
Children, adolescents, or adults who are being considered for treatment with stimulant medications should
have a careful history (including assessment for a family history of sudden death or ventricular
arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further
cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive
of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in
patients with a pre-existing psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar
disorder because of concern for possible induction of a mixed/ manic episode in such patients. Prior to
initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a detailed
psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in
children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants
at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the
stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-
term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of
3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated
patients compared to 0 in placebo-treated patients.
Aggression
Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been
reported in clinical trials and the postmarketing experience of some medications indicated for the
treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior
or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or
worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either
methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups
of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10
to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout
the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height
and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of
development. Published data are inadequate to determine whether chronic use of amphetamines may cause
a similar suppression of growth, however, it is anticipated that they likely have this effect as well.
Therefore, growth should be monitored during treatment with stimulants, and patients who are not
growing or gaining height or weight as expected may need to have their treatment interrupted.
Seizures
There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior
history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures,
the drug should be discontinued.
Peripheral Vasculopathy, including Raynaud’s phenomenon
Stimulants, including Ritalin and Ritalin SR, used to treat ADHD are associated with peripheral
vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild;
however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral
vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different
times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms
generally improve after reduction in dose increase or discontinuation of drug. Careful observation for
digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g.,
rheumatology referral) may be appropriate for certain patients.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Use in Children Under Six Years of Age
Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not
been established.
Drug Dependence
Ritalin should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic
abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal
behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is
required during withdrawal from abusive use, since severe depression may occur. Withdrawal following
chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.
PRECAUTIONS
Patients with an element of agitation may react adversely; discontinue therapy if necessary.
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in
light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend
on the physician’s assessment of the chronicity and severity of the child’s symptoms and their
appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of
the behavioral characteristics.
When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not
indicated.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about
the benefits and risks associated with treatment with methylphenidate and should counsel them in its
appropriate use. A patient Medication Guide is available for Ritalin and Ritalin-SR. The prescriber or
health professional should instruct patients, their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients should be given the opportunity to
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The
complete text of the Medication Guide is reprinted at the end of this document.
Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]
• Instruct patients beginning treatment with Ritalin or Ritalin SR about the risk of peripheral
vasculopathy, including Raynaud’s Phenomenon, and in associated signs and symptoms: fingers or
toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red
• Instruct patients to report to their physician any new numbness, pain, skin color change, or
sensitivity to temperature in fingers or toes
• Instruct patients to call their physician immediately with any signs of unexplained wounds
appearing on fingers or toes while taking Ritalin or Ritalin SR
Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients
Drug Interactions
Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with
MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible
effects on blood pressure, Ritalin should be used cautiously with pressor agents.
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is
metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways.
Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of
coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs
(e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be
required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and
monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or
discontinuing methylphenidate.
Carcinogenesis/Mutagenesis/Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in
hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of
approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum
recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare
rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain
used is sensitive to the development of hepatic tumors, and the significance of these results to humans is
unknown.
Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in
F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5
times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic
carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing
the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups
were exposed to 60-74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse
lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were
Reference ID: 3321241
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increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster
Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone
marrow micronucleus assay.
Methlyphenidate did not impair fertility in male or female mice that were fed diets containing the drug in
an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day,
approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis,
respectively.
PREGNANCY
Pregnancy Category C
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and
200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence
of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the
maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal
development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence
of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen
at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no
effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2
basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up
to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a
mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre-
and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis).
Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised if Ritalin is administered to a nursing woman.
Pediatric Use
Ritalin should not be used in children under six years of age (see WARNINGS).
In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100
mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through
sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14),
decreased spontaneous locomotor activity was observed in males and females previously treated with 50
mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis)
or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the
highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral
development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the
long-term behavioral effects observed in rats is unknown.
ADVERSE REACTIONS
Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing
dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity
(including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with
Reference ID: 3321241
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histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea;
dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and
down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy.
There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. Although a
definite causal relationship has not been established, the following have been reported in patients taking
this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma;
isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood;
aggressive behavior; a few instances of scalp hair loss. Very rare reports of neuroleptic malignant
syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies
associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for
approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of
venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug
alone, or some other cause.
In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and
tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also
occur.
DOSAGE AND ADMINISTRATION
Dosage should be individualized according to the needs and responses of the patient.
Adults
Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals.
Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg
daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take
the last dose before 6 p.m.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR
tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the
titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or
chewed.
Children (6 years and over)
Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is
not recommended.
If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug
should be discontinued.
Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg
weekly.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR
tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the
titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or
chewed.
If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary,
discontinue the drug.
Reference ID: 3321241
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Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained
when the drug is either temporarily or permanently discontinued.
Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.
OVERDOSAGE
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central
nervous system and from excessive sympathomimetic effects, may include the following: vomiting,
agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria,
confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations,
cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.
Treatment consists of appropriate supportive measures. The patient must be protected against self-injury
and against external stimuli that would aggravate overstimulation already present. Gastric contents may be
evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a
short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include
administration of activated charcoal and a cathartic.
Intensive care must be provided to maintain adequate circulation and respiratory exchange; external
cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been
established.
HOW SUPPLIED
Tablets 5 mg - round, yellow (imprinted CIBA 7)
Bottles of 100 ...............................................……………………………......NDC 0078-0439-05
Tablets 10 mg - round, pale green, scored (imprinted CIBA 3)
Bottles of 100 .................................................................................................NDC 0078-0440-05
Tablets 20 mg - round, pale yellow, scored (imprinted CIBA 34)
Bottles of 100 .......………………………………………………………......NDC 0078-0441-05
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from light.
Dispense in tight, light-resistant container (USP).
SR Tablets 20 mg - round, white, coated (imprinted CIBA 16)
Bottles of 100……………………………………………………………...NDC 0078-0442-05
Note: SR Tablets are color-additive free.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from moisture.
Dispense in tight, light-resistant container (USP).
MEDICATION GUIDE
RITALIN®
(methylphenidate hydrochloride tablets, USP) CII
Reference ID: 3321241
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Read the Medication Guide that comes with RITALIN® before you or your child starts taking it and each time you
get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor
about your or your child’s treatment with RITALIN® .
What is the most important information I should know about RITALIN®?
The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines.
1. Heart-related problems:
• sudden death in patients who have heart problems or heart defects
• stroke and heart attack in adults
• increased blood pressure and heart rate
Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history
of these problems.
Your doctor should check you or your child carefully for heart problems before starting RITALIN® .
Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with
RITALIN® .
Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness
of breath, or fainting while taking RITALIN® .
2. Mental (Psychiatric) problems:
All Patients
• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility
Children and Teenagers
• new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or
new manic symptoms
Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar
illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems
while taking RITALIN®, especially seeing or hearing things that are not real, believing things that are not
real, or are suspicious.
3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s
phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to
red
• Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to
temperature in the fingers or toes.
• Call your doctor right away if you have or your child has any signs of unexplained wounds
appearing on fingers or toes while taking Ritalin
What Is RITALIN®?
RITALIN® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-
Deficit Hyperactivity Disorder (ADHD). RITALIN® may help increase attention and decrease impulsiveness and
hyperactivity in patients with ADHD.
Reference ID: 3321241
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For current labeling information, please visit https://www.fda.gov/drugsatfda
RITALIN® should be used as a part of a total treatment program for ADHD that may include counseling or other
therapies.
RITALIN® is also used in the treatment of a sleep disorder called narcolepsy.
RITALIN® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep
RITALIN® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN® may harm others,
and is against the law.
Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol,
prescription medicines or street drugs.
Who should not take RITALIN®?
RITALIN® should not be taken if you or your child:
• are very anxious, tense, or agitated
• have an eye problem called glaucoma
• have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated
movements or sounds.
• are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase
inhibitor or MAOI.
•
are allergic to anything in RITALIN® . See the end of this Medication Guide for a complete list of ingredients.
RITALIN® should not be used in children less than 6 years old because it has not been studied in this age group.
RITALIN® may not be right for you or your child. Before starting RITALIN® tell your or your child’s
doctor about all health conditions (or a family history of) including:
• heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar illness, or depression
• tics or Tourette’s syndrome
• seizures or have had an abnormal brain wave test (EEG)
•
circulation problems in fingers or toes
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding.
Can RITALIN® be taken with other medicines?
Tell your doctor about all of the medicines that you or your child take including prescription and
nonprescription medicines, vitamins, and herbal supplements. RITALIN® and some medicines may interact
with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted
while taking RITALIN® .
Your doctor will decide whether RITALIN® can be taken with other medicines.
Especially tell your doctor if you or your child takes:
• anti-depression medicines including MAOIs
• seizure medicines
• blood thinner medicines
• blood pressure medicines
• cold or allergy medicines that contain decongestants
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and
pharmacist.
Do not start any new medicine while taking RITALIN® without talking to your doctor first.
How should RITALIN® be taken?
• Take RITALIN® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.
Reference ID: 3321241
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Ritalin is usually taken 2 to 3 times a day.
• Take RITALIN® 30 to 45 minutes before a meal.
• From time to time, your doctor may stop RITALIN® treatment for a while to check ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN® . Children
should have their height and weight checked often while taking RITALIN® . RITALIN® treatment may be
stopped if a problem is found during these check-ups.
• If you or your child takes too much RITALIN® or overdoses, call your doctor or poison control center
right away, or get emergency treatment.
What are possible side effects of RITALIN®?
See “What is the most important information I should know about RITALIN®?” for information on reported
heart and mental problems.
Other serious side effects include:
• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision
Common side effects include:
• headache
• decreased appetite
• stomach ache
• nervousness
• trouble sleeping
• nausea
Talk to your doctor if you or your child has side effects that are bothersome or do not go away.
This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.
How should I store RITALIN®?
• Store RITALIN in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from light.
• Keep RITALIN® and all medicines out of the reach of children.
General information about RITALIN®
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
RITALIN® for a condition for which it was not prescribed. Do not give RITALIN® to other people, even if they have
the same condition. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about RITALIN®. If you would like more
information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN® that
was written for healthcare professionals. For more information about RITALIN® call 1-888-669-6682.
What are the ingredients in RITALIN®?
Active Ingredient: methylphenidate HCL
Inactive Ingredients: D&C Yellow No.10 (5-mg and 20-mg tablets), FD&C Green No.3 (10-mg tablets), lactose,
magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg
tablets).
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reference ID: 3321241
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For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
RITALIN-SR®
(methylphenidate hydrochloride, USP) sustained-release tablets CII
Read the Medication Guide that comes with RITALIN-SR® before you or your child starts taking it and each time
you get a refill. There may be new information. This Medication Guide does not take the place of talking to your
doctor about your or your child’s treatment with RITALIN-SR® .
What is the most important information I should know about RITALIN-SR®?
The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines.
1. Heart-related problems:
• sudden death in patients who have heart problems or heart defects
• stroke and heart attack in adults
• increased blood pressure and heart rate
Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history
of these problems.
Your doctor should check you or your child carefully for heart problems before starting RITALIN-SR® .
Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with
RITALIN-SR® .
Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness
of breath, or fainting while taking RITALIN-SR® .
2. Mental (Psychiatric) problems:
All Patients
• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility
Children and Teenagers
• new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or
new manic symptoms
Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar
illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems
while taking RITALIN-SR®, especially seeing or hearing things that are not real, believing things that are not
real, or are suspicious.
3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s
phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to
red
• Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to
temperature in the fingers or toes.
• Call your doctor right away if you have or your child has any signs of unexplained wounds
appearing on fingers or toes while taking Ritalin-SR
What Is RITALIN-SR®?
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RITALIN-SR® is a central nervous system stimulant prescription medicine. It is used for the treatment of
Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN-SR® may help increase attention and decrease
impulsiveness and hyperactivity in patients with ADHD.
RITALIN-SR® should be used as a part of a total treatment program for ADHD that may include counseling or other
therapies.
RITALIN-SR® is also used in the treatment of a sleep disorder called narcolepsy.
RITALIN-SR® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep
RITALIN-SR® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN-SR® may harm
others, and is against the law.
Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol,
prescription medicines or street drugs.
Who should not take RITALIN-SR®?
RITALIN-SR® should not be taken if you or your child:
• are very anxious, tense, or agitated
• have an eye problem called glaucoma
• have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated
movements or sounds.
• are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase
inhibitor or MAOI.
• are allergic to anything in RITALIN-SR® . See the end of this Medication Guide for a complete list of
ingredients.
RITALIN-SR® should not be used in children less than 6 years old because it has not been studied in this age group.
RITALIN-SR® may not be right for you or your child. Before starting RITALIN-SR® tell your or your
child’s doctor about all health conditions (or a family history of) including:
• heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar illness, or depression
• tics or Tourette’s syndrome
• seizures or have had an abnormal brain wave test (EEG)
•
circulation problems in fingers or toes
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding.
Can RITALIN-SR® be taken with other medicines?
Tell your doctor about all of the medicines that you or your child take including prescription and
nonprescription medicines, vitamins, and herbal supplements. RITALIN-SR® and some medicines may interact
with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted
while taking RITALIN-SR® .
Your doctor will decide whether RITALIN-SR® can be taken with other medicines.
Especially tell your doctor if you or your child takes:
• anti-depression medicines including MAOIs
• seizure medicines
• blood thinner medicines
• blood pressure medicines
• cold or allergy medicines that contain decongestants
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and
pharmacist.
Do not start any new medicine while taking RITALIN-SR® without talking to your doctor first.
How should RITALIN-SR® be taken?
• Take RITALIN-SR® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your
child.
• Take RITALIN-SR® 30 to 45 minutes before a meal. The effect of a dose of RITALIN-SR usually lasts about 8
hours.
• Do not chew or crush RITALIN-SR® tablets. Swallow RITALIN-SR® tablets whole with water or other
liquids. Tell your doctor if you or your child cannot swallow RITALIN-SR® whole. A different medicine may
need to be prescribed.
• From time to time, your doctor may stop RITALIN-SR® treatment for a while to check ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN-SR® .
Children should have their height and weight checked often while taking RITALIN-SR® . RITALIN-SR®
treatment may be stopped if a problem is found during these check-ups.
• If you or your child takes too much RITALIN-SR® or overdoses, call your doctor or poison control center
right away, or get emergency treatment.
What are possible side effects of RITALIN-SR®?
See “What is the most important information I should know about RITALIN-SR®?” for information on
reported heart and mental problems.
Other serious side effects include:
• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision
Common side effects include:
• headache
• decreased appetite
• stomach ache
• nervousness
• trouble sleeping
• nausea
Talk to your doctor if you or your child has side effects that are bothersome or do not go away.
This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.
How should I store RITALIN-SR®?
• Store RITALIN-SR® in a safe place at room temperature, 59 to 86° F (15 to 30° C). Protect from moisture.
• Keep RITALIN-SR® and all medicines out of the reach of children.
General information about RITALIN-SR®
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
RITALIN-SR® for a condition for which it was not prescribed. Do not give RITALIN-SR® to other people, even if
they have the same condition. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about RITALIN-SR®. If you would like more
information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN-SR® that
was written for healthcare professionals. For more information about RITALIN-SR call 1-888-669-6682.
What are the ingredients in RITALIN-SR®?
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Active Ingredient: methylphenidate HCL, USP
Inactive Ingredients: cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone,
titanium dioxide, and zein
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
REV: Month Year
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
Reference ID: 3321241
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:30.259092
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/010187s074,018029s044lbl.pdf', 'application_number': 18029, 'submission_type': 'SUPPL ', 'submission_number': 44}
|
11,117
|
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 4
Baxter
OSMITROL Injection (Mannitol Injection, USP)
in AVIVA Plastic Container
For Therapeutic Use Only
Description
Osmitrol Injection (Mannitol Injection, USP) is a sterile, nonpyrogenic solution of Mannitol, USP in a
single dose container for intravenous administration. It contains no antimicrobial agents. Mannitol**
is a six carbon sugar alcohol prepared commercially by the reduction of dextrose. Although virtually
inert metabolically in humans, it occurs naturally in fruits and vegetables. Mannitol is an obligatory
osmotic diuretic. The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.
Composition, osmolarity, and pH are shown in Table 1.
Composition
Table 1
Size
(mL)
**Mannitol,
USP (g/L)
*Osmolarity
(mOsmol/L)
(calc)
pH
5%
OSMITROL
Injection (5%
Mannitol
Injection, USP)
1000
50
274
5.5
(4.5 TO 7.0)
500
10%
OSMITROL
Injection (10%
Mannitol
Injection, USP)
1000
100
549
5.5
(4.5 TO 7.0)
15%
OSMITROL
Injection (15%
Mannitol
Injection, USP)
500
150
823
5.5
(4.5 TO 7.0)
250
20%
OSMITROL
Injection (20%
Mannitol
Injection, USP)
500
200
1098
5.5
(4.5 TO 7.0)
*Normal physiologic osmolarity range is approximately 280 to 310 m0smol/L.
Administration of substantially hypertonic solutions (≥ 600 m0smol/L) may cause vein damage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 5
Mannitol
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for the attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Osmitrol Injection (Mannitol Injection, USP) is one of the nonelectrolyte, obligatory, osmotic
diuretics. It is freely filterable at the renal glomerulus, only poorly reabsorbed by the renal tubule, not
secreted by the tubule, and is pharmacologically inert.
Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small
molecular size being largely confined to the extracellular space. Only relatively small amounts of the
dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney
over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a
100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even
at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted
by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 6
and chloride by elevating the osmolarity of the glomerular filtrate.
This increase in extracellular osmolarity effected by the intravenous administration of mannitol will
induce the movement of intracellular water to the extracellular and vascular spaces. This action
underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated
intraocular pressure.
Indications and Usage
Osmitrol Injection (Mannitol Injection, USP) is indicated for:
The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal
failure before irreversible renal failure becomes established;
The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass;
The reduction of elevated intraocular pressure when the pressure cannot be lowered by other means,
and promoting the urinary excretion of toxic substances.
Contraindications
Osmitrol Injection (Mannitol Injection, USP) is contraindicated in patients with:
Well established anuria due to severe renal disease, severe pulmonary congestion or frank pulmonary
edema, active intracranial bleeding except during craniotomy, severe dehydration,Progressive renal
damage or dysfunction after institution of mannitol therapy, including increasing oliguria and
azotemia, and progressive heart failure or pulmonary congestion after institution of mannitol therapy.
Warnings
In patients with severe impairment of renal function, a test dose should be utilized (see Dosage and
Administration). A second test dose may be tried if there is an inadequate response, but no more than
two test doses should be attempted.
The obligatory diuretic response following rapid infusion of 15% or 20% mannitol injection may
further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to
serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol
administration.
If urine output continues to decline during mannitol infusion, the patient’s clinical status should be
closely reviewed and mannitol infusion suspended if necessary. Accumulation of mannitol may result
in overexpansion of the extracellular fluid which may intensify existing or latent congestive heart
failure.
Excessive loss of water and electrolytes may lead to serious imbalances. With continued
administration of mannitol, loss of water in excess of electrolytes can cause hypernatremia. Electrolyte
measurements, including sodium and potassium, are therefore, of vital importance in monitoring the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 7
infusion of mannitol.
Osmotic nephrosis, a reversible vacuolization of the tubules of unknown clinical significance, may
proceed to severe irreversible nephrosis, so that the renal function must be closely monitored during
mannitol infusion.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
The cardiovascular status of the patient should be carefully evaluated before rapidly administrating
mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart
failure.
Shift of sodium free intracellular fluid into the extracellular compartment following mannitol infusion
may lower serum sodium concentration and aggravate preexisting hyponatremia.
By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or
hypovolemia.
Electrolyte free mannitol should not be given conjointly with blood. If it is essential that blood be
given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol
solution to avoid pseudoagglutination.
When exposed to low temperatures, solutions of mannitol may crystallize. Concentrations greater than
15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals
are visible, redissolve by warming the solution up to 70°C, with agitation. Allow the solution to cool
to room temperature before reinspection for crystals. Administer intravenously using sterile, filter-
type administration set.
Laboratory Tests
Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 8
The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or
hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding
excessive fluid and electrolyte shifts. The routine features of physical examination and clinical
chemistries suffice in achieving an adequate degree of appropriate patient monitoring.
Drug Interaction
Studies have not been conducted to evaluate drug/drug or drug/food interactions with Osmitrol
Injection (Mannitol Injection, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Osmitrol Injection (Mannitol Injection, USP) have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with mannitol. It is also
not known whether mannitol can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. Mannitol should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Osmitrol Injection (Mannitol Injection,
USP) on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when mannitol is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in children below the age of 12 have not been established.
Usage in Children
Dosage requirements for patients 12 years of age and under have not been established.
Geriatric Use
Clinical studies of Osmitrol Injection (Mannitol Injection, USP) did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 9
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Extensive use of mannitol over the last several decades has produced recorded adverse events, in a
variety of clinical settings, that are isolated or idiosyncratic in nature. None of these adverse reactions
have occurred with any great frequency nor with any security in attributing them to mannitol.
The inability to clearly exclude the drug related nature of such events in these isolated reports prompts
the necessity to list the reactions that have been observed in patients during or following mannitol
infusion. In this fashion, patients have exhibited nausea, vomiting, rhinitis, local pain, skin necrosis
and thrombophlebitis at the site of infection, chills, dizziness, urticaria, hypotension, hypertension,
tachycardia, fever and angina-like chest pains.
Of far greater clinical significance is a variety of events that are related to inappropriate recognition
and monitoring of fluid shifts. These are not intrinsic adverse reactions to the drug but the
consequence of manipulating osmolarity by any agency in a therapeutically inappropriate manner.
Failure to recognize severe impairment of renal function with the high likelihood of nondiuretic
response can lead to aggravated dehydration of tissues and increased vascular fluid load. Induced
diuresis in the presence of preexisting hemoconcentration and preexisting deficiency of water and
electrolytes can lead to serious imbalances. Expansion of the extracellular space can aggravate cardiac
decompensation or induce it in the presence of latent heart failure. Pulmonary congestion or edema
can be seriously aggravated with the expansion of the extracellular and therefore intravascular fluid
load. Hemodilution and dilution of the extracellular fluid space by osmotic shift of water can induce or
aggravate preexisting hyponatremia.
If unrecognized, such fluid and/or electrolyte shift can produce the reported adverse reactions of
pulmonary congestion, acidosis, electrolyte loss, dryness of mouth, thirst, edema, headache, blurred
vision, convulsions and congestive cardiac failure.
These are not truly adverse reactions to the drug and can be appropriately prevented by evaluation of
degree of renal failure with a test dose response to mannitol when indicated; evaluation of
hypervolemia and hypovolemia; sodium and potassium levels; hemodilution or hemoconcentration;
and evaluation of renal, cardiac and pulmonary function at the onset of therapy.
Dosage and Administration
Osmitrol Injection (Mannitol Injection, USP) should be administered only by intravenous infusion.
The total dosage, concentration, and rate of administration should be governed by the nature and
severity of the condition being treated, fluid requirement, and urinary output. The usual adult dosage
ranges from 20 to 100 g in a 24 hour period, but in most instances an adequate response will be
achieved at a dosage of approximately 50 to 100 g in a 24 hour period. The rate of administration is
usually adjusted to maintain a urine flow of at least 30 to 50 mL/hour. This outline of administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 10
and dosage is only a general guide to therapy.
Parenteral dug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of a final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
Test Dose: A test dose of mannitol should be given prior to instituting Osmitrol Injection (Mannitol
Injection, USP) therapy for patients with marked oliguria, or those believed to have inadequate renal
function. Such a test dose may be approximately 0.2 g/kg body weight (about 75 mL of a 20%
solution or 100 mL of a 15% solution) infused in a period of three to five minutes to produce a urine
flow of at least 30 to 50 mL/hour. If urine flow does not increase, a second test dose may be given; if
there is an inadequate response, the patient should be reevaluated.
Prevention of Acute Renal Failure (Oliguria): When used during cardiovascular and other types of
surgery, 50 to 100 g of mannitol as a 5, 10, or 15% solution may be given. The concentration will
depend upon the fluid requirements of the patient.
Treatment of Oliguria: The usual dose for treatment of oliguria is 100 g administered as a 15 or 20%
solution.
Reduction of Intraocular Pressure: A dose of 1.5 to 2.0 g/kg as a 20% solution (7.5 to 10 mL/kg) or as
a 15% solution (10 to 13 mL/kg) may be given over a period as short as 30 minutes in order to obtain a
prompt and maximal effect. When used preoperatively the dose should be given one to one and one-
half hours before surgery to achieve maximal reduction of intraocular pressure before operation.
Reduction of Intracranial Pressure: Usually a maximum reduction in intracranial pressure in adults can
be achieved with a dose of 0.25 g/kg given not more frequently than every six to eight hours. An
osmotic gradient between the blood and cerebrospinal fluid of approximately 10 m0smols will yield a
satisfactory reduction in intracranial pressure.
Adjunctive Therapy for Intoxications: As an agent to promote diuresis in intoxications, 5%, 10%, 15%
or 20% mannitol is indicated. The concentration will depend upon the fluid requirement and urinary
output of the patient.
Measurement of glomerular filtration rate by creatinine clearance may be useful for determination of
dosage.
All injections in AVIVA containers are intended for intravenous administration using sterile
equipment.
The use of supplemental additive medication is not recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 11
How Supplied
Osmitrol Injection (Mannitol Injection, USP) in AVIVA plastic containers is available as follows:
Code
Size (mL)
NDC
Product Name
6E5604
1000
0338-6300-04
5% Osmitrol Injection
(5% Mannitol Injection, USP)
6E5613
6E5614
500
1000
0338-6301-03
0338-6301-04
10% Osmitrol Injection
(10% Mannitol Injection, USP)
6E5623
500
0338-6302-03
15% Osmitrol Injection
(15% Mannitol Injection, USP)
6E5632
6E5633
250
500
0338-6303-02
0338-6303-03
20% Osmitrol Injection
(20% Osmitrol Injection)
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 12
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, OSMITROL, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 13
Baxter
Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below.
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an
osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an
osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 14
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis
procedures.
Contraindications
None known.
Warnings
Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
In patients with diminished renal function, administration of Sodium Chloride Injection, USP may
result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 15
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride
Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in
the pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in the responses between elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 16
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
The available sizes of each injection in AVIVA plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
6E1313
500
0338-6333-03
0.45% Sodium Chloride Injection,
USP
6E1314
1000
0338-6333-04
6E1356
250
0338-6333-02
6E1322
250
0338-6304-02
0.9% Sodium Chloride Injection,
USP
6E1323
500
0338-6304-03
6E1324
1000
0338-6304-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C/77°F); brief exposure up to
40°C(104°F) does not adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 17
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
For Product Information
1-800-833-0303
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 18
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 19
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 20
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 21
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 22
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 23
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 24
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 25
Baxter
Lactated Ringer’s and 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
Each 100 mL contains 5 g Dextrose Hydrous, USP*; 600 mg Sodium Chloride, USP (NaCl); 310 mg
Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride,
USP (CaCl2•2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of
water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq
potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L
(calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions may cause vein damage. The caloric content is 180 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 26
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate
ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of
hydrogen cations.
Indications and Usage
Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and
calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care. If at all, in patients
with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists
edema with sodium retention.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients
with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care in patients with
metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in
those conditions in which there is an increased level or an impaired utilization of these ions, such as
severe hepatic insufficiency.
Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with
blood through the same administration set because of the likelihood of coagulation.
The intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid
and/or solute overloading resulting is dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 27
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Lactated Ringer’s and 5% Dextrose
Injection, USP may result in sodium or potassium retention.
Lactated Ringer’s and 5% Dextrose Injection, USP is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt
or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Lactated Ringer's and 5% Dextrose Injection, USP
to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Lactated Ringer's and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 28
Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s
and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Lactated Ringer's and 5% Dextrose
Injection, USP on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Lactated Ringer’s and 5% Dextrose Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients
have not been established by adequate and well controlled trials, however, the use of lactated ringer’s
and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum amorality and possible hemorrhage.
Geriatric Use
Clinical studies of Lactated Ringer’s and 5% Dextrose Injection, USP did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in the responses between
elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Allergic reactions or anaphylactic symptoms such as localized or generalized urinary and purities; per
orbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 29
reported during administration of Lactated Ringer’s and 5% Dextrose Injection, USP. The reporting
frequency of these signs and symptoms is higher in women during pregnancy.
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasations, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown
below:
Code
Size
NDC
6E2073
500 mL
NDC 0338-6306-03
6E2074
1000 mL
NDC 0338-6306-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 30
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 31
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 32
Baxter
Lactated Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
Composition (g/L)
Ionic Concentration (mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP, (NaCl)
Sodium Lactate, (C3H5NaO3)
Potassium Chloride, USP, (KCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
Lactate
Caloric Content
(kcal/L)
250
500
Lactated
Ringer’s
Injection, USP
1000
6
3.1
0.3
0.2
273
6.5
(6.0 to 7.5)
130
4
2.7
109
28
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 33
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are
metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen
cations.
Indications and Usage
Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing
agent.
Contraindications
None known
Warnings
Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Lactated Ringer’s Injection, USP should be used with great care in patients with metabolic or
respiratory alkalosis. The administration of lactate ions should be done with great care in those
conditions in which there is an increased level or an impaired utilization of these ions, such as severe
hepatic insufficiency.
Lactated Ringer’s Injection, USP should not be administered simultaneously with blood through the
same administration set because of the likelihood of coagulation.
The intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute
overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states,
or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte
concentration of the injections. The risk of solute overload causing congested states with peripheral
and pulmonary edema is directly proportional to the electrolyte concentrations of the injections.
In patients with diminished renal function, administration of Lactated Ringer’s Injection, USP may
result in sodium or potassium retention. Lactated Ringer’s injection, USP is not for use in the
treatment of lactic acidosis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 34
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Lactated Ringer’s Injections, USP must be used with caution. Excess administration may result in
metabolic alkalosis.
Laboratory Test
CLINICAL EVALUATION AND PERIODIC LABORATORY DETERMINATIONS ARE NECESSARY TO MONITOR
CHANGES IN FLUID BALANCE, ELECTROLYTE CONCENTRATIONS, AND ACID BASE BALANCE DURING
PROLONGED PARENTERAL THERAPY OR WHENEVER THE CONDITION OF THE PATIENT WARRANTS SUCH
EVALUATION.
Drug Interactions
Caution must be exercised in the administration of Lactated Ringer's Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Lactated Ringer's Injection, USP.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
STUDIES WITH LACTATED RINGER'S INJECTION, USP HAVE NOT BEEN PERFORMED TO EVALUATE
CARCINOGENIC POTENTIAL, MUTAGENIC POTENTIAL, OR EFFECTS ON FERTILITY.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s
Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Lactated Ringer's Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 35
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Lactated Ringer's Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of electrolyte solutions in the
pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Lactated Ringer’s Injection, USP did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function and concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Allergic reactions or anaphylactoid symptoms such as localized or generalized urticaria and pruritis;
periorbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have
been reported during administration of Lactated Ringer’s Injection, USP. The reporting frequency of
these signs and symptoms is higher in women during pregnancy.
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
infection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 36
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2322
250
0338-6307-02
6E2323
500
0338-6307-03
6E2324
1000
0338-6307-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40° C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 37
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 38
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 39
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 40
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 41
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 42
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 43
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 44
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 45
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 46
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 47
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 48
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 49
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 50
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 51
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 52
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 53
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 54
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 55
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 56
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 57
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 58
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 59
Baxter
Sodium Lactate Injection, USP (M/6 Sodium Lactate)
in AVIVA Plastic Container
Description
Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition,
osmolarity, pH, ionic concentration and caloric content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
Size
(mL)
Sodium Lactate
(C3H5NaO3)
*Osmolarity
(mOsmol/L)
(calc)
pH
Sodium
Lactate
Caloric Content
(kcal/L)
500
Sodium
Lactate
Injection, USP
(M/6 Sodium
Lactate)
1000
18.7
334
6.5
(6.0 to 7.3)
167
167
54
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 60
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable
of inducing diuresis depending on the clinical condition of the patient.
Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized
ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an
alkalinizing agent.
Contraindications
None known
Warnings
Sodium Lactate Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Sodium Lactate Injection, USP should be used with great care in patients with metabolic or respiratory
alkalosis. The administration of lactate ions should be done with great care in those conditions in
which there is an increased level or an impaired utilization of these ions, such as severe hepatic
insufficiency.
The intravenous administration of these injections can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
Excessive administration of Sodium Lactate Injection, USP may result in significant hypokalemia.
In patients with diminished renal function, administration of Sodium Lactate Injection, USP may result
in sodium retention.
Sodium Lactate Injection, USP is not for use in the treatment of lactic acidosis.
Precautions
General
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 61
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Sodium Lactate Injection, USP (M/6 Sodium
Lactate) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Lactate Injection, USP (M/6 Sodium Lactate).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Lactate Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Lactate
Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP (M/6
Sodium Lactate) on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Sodium Lactate Injection, USP is administered to a
nursing mother.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 62
Pediatric Use
Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of sodium lactate solutions in the
pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Lactate Injection, USP did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of a final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 63
How Supplied
Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA plastic container is available as
follows:
Code
Size (mL)
NDC
6E1803
500
0338-6311-03
6E1804
1000
0338-6311-04
EXPOSURE OF PHARMACEUTICAL PRODUCTS TO HEAT SHOULD BE MINIMIZED. AVOID EXCESSIVE
HEAT. IT IS RECOMMENDED THE PRODUCT BE STORED AT ROOM TEMPERATURE (25°C); BRIEF
EXPOSURE UP TO 40°C DOES NOT ADVERSELY AFFECT THE PRODUCT.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 64
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 65
Baxter
Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in
single dose containers for intravenous administration. It contains no antimicrobial agents. The pH
may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration
are shown in Table 1.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP (NaCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Potassium Chloride, USP (KCl)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
500
Ringer’s
Injection,
USP
1000
8.6
0.33
0.3
309
5.5
(5.0 to 7.5)
147.5
4
4.5
156
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 66
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing
diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart
failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe
renal failure, and in conditions in which potassium retention is present.
Ringer’s Injection, USP should not be administered simultaneously with blood through the same
administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading
resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 67
edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the
injection. The risk of solute overload causing congested states with peripheral and pulmonary edema
is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s Injection, USP may result in
sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving
corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer’s Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential,
mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection,
USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a
pregnant woman only if clearly needed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 68
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and
delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by
adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 69
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2303
500
NDC 0338-6312-03
6E2304
1000
NDC 0338-6312-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 70
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 71
Baxter
Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in
single dose containers for intravenous administration. It contains no antimicrobial agents. The pH
may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration
are shown in Table 1.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP (NaCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Potassium Chloride, USP (KCl)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
500
Ringer’s
Injection,
USP
1000
8.6
0.33
0.3
309
5.5
(5.0 to 7.5)
147.5
4
4.5
156
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 72
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing
diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart
failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe
renal failure, and in conditions in which potassium retention is present.
Ringer’s Injection, USP should not be administered simultaneously with blood through the same
administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading
resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary
edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the
injection. The risk of solute overload causing congested states with peripheral and pulmonary edema
is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s Injection, USP may result in
sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 73
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving
corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer’s Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential,
mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection,
USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and
delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Ringer’s Injection, USP is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by
adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 74
Geriatric Use
Clinical studies of Ringer’s Injection, USP did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2303
500
NDC 0338-6312-03
6E2304
1000
NDC 0338-6312-04
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 75
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 76
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 77
Baxter
Ringer’s and 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Ringer’s and 5% Dextrose Injection, USP is sterile, nonpyrogenic solution for fluid and electrolyte
replenishment and caloric supply in a single dose container for intravenous administration. Each 100
mL contains 5 g Dextrose Hydrous, USP*; 860 mg of Sodium Chloride, USP (NaCl); 33 mg of
Calcium Chloride, USP (CaCl2•2H2O); and 30 mg of Potassium Chloride, USP (KCl). It contains no
antimicrobial agents. The pH is 4.0 (3.5 to 6.5).
c
*
D-Glucopyranose monohydrate
Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water,
electrolytes, and calories. One liter has an ionic concentration of 147.5 mEq sodium, 4.5 mEq calcium,
4 mEq potassium, and 156 mEq chloride. The osmolarity is 561 mOsmol/L (calc). Normal
physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions may cause vein damage. The caloric content is 170 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 78
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It
is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood
through the same administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or
solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested
states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte
concentrations of the injection. The risk of solute overload causing congested states with peripheral
and pulmonary edema is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s and 5% Dextrose Injection, USP
may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 79
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Ringer's and 5% Dextrose Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer's and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer's and 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer's and 5%
Dextrose Injection, USP. It is also not known whether Ringer's and 5% Dextrose Injection, USP can
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer's
and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer's and 5% Dextrose Injection, USP on
labor and delivery. Caution should be exercised when administering this drug during labor and
delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Ringer's and 5% Dextrose Injection, USP is
administered to a nursing woman.
Pediatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 80
Safety and effectiveness of Ringer's and 5% Dextrose Injection, USP in pediatric patients have not
been established by adequate and well controlled trials, however, the use of ringer's and dextrose
solutions in the pediatric population is referenced in the medical literature. The warnings, precautions
and adverse reactions identified in the label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Ringer's and 5% Dextrose Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 81
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Ringer's and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2064
1000
NDC 0338-6313-04
6E2063
500
NDC 0338-6313-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C): brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 82
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter Healthcare International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 83
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 84
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 85
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 86
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 87
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 88
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 89
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 90
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 91
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 92
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injections.
Excessive administration of Dextrose and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Dextrose and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 93
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 94
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 95
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 96
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 97
Baxter
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1,
USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile,
nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL
contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl);
and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH
is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0).
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq
acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions may cause vein damage. The caloric content is 21 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 98
Clinical Pharmacology
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic
alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water,
which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source
of water and electrolytes or as an alkalinizing agent.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with
blood or blood components. It may be administered prior to or following the infusion of blood through
the same administration set (i.e., as a priming solution), added to or infused concurrently with blood
components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148
Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood
components.
Contraindications
None known
Warnings
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical
states in which there exists edema with sodium retention.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which
potassium retention is present.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care in patients with metabolic or respiratory alkalosis. The administration of acetate or
gluconate ions should be done with great care in those conditions in which there is an increased level
or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection,
Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 99
In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-
LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection
(Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly
needed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 100
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE 148 Injection (Multiple Electrolytes
Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) did
not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 101
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2534
1000
NDC 0338-6316-04
6E2533
500
NDC 0338-6316-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 102
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 103
Baxter
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection,
Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile,
nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL
contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl);
and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH
is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0).
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a sousrce of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq
acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic
osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may
cause vein damage. The caloric content is 21 lcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 104
Clinical Pharmacology
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a
source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition
of the patient.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a
metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide
and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a
source of water and electrolytes or as an alkalinizing agent.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with
blood or blood components. It may be administered prior to or following the infusion of blood through
the same administration set (i.e., as a priming solution), added to or infused concurrently with blood
components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A
Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood
components.
Contraindications
None known
Warnings
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in
clinical states in which there exists edema with sodium retention.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which
potassium retention is present.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or
gluconate ions should be done with great care in those conditions in which there is an increased level
or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes
Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional
states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 105
overload causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4
(Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) have
not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal
harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 106
A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE A Injection pH 7.4
(Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised
when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE A Injection pH 7.4 (Multiple
Electrolytes Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type
1, USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP)
did not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elkerly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 107
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2544
1000
NDC 0338-6317-04
6E2543
500
NDC 0338-6317-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 108
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 109
Baxter
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 234 mg Sodium Chloride, USP (NaCl); 128 mg Potassium Acetate, USP (C2H3KO2); and 32 mg
Magnesium Acetate, Tetrahydrate (C4H6MgO4•4H2O). It contains no antimicrobial agents. pH 5.0
(4.0 to 6.5). The pH is adjusted with hydrochloric acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq
chloride, and 16 mEq acetate. The osmolarity is 363 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 170 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 110
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon
dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of acetate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 111
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should not be administered simultaneously with blood through the same administration set
because of the possibility of pseudoagglutination or hemolysis.
The intravenous administration of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 56 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 56 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 112
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also
not known whether PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE 56 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 113
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 114
6E2573
500
NDC 0338-6318-03
6E2574
1000
NDC 0338-6318-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 115
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 116
Baxter
PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 161 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 138 mg Sodium Lactate
(C3H5NaO3), 119 mg Potassium Chloride, USP (KCl), 94 mg Sodium Chloride, USP (NaCl), 37 mg
Calcium Chloride, USP (CaCl2•2H2O), and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It
contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric
acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 16 mEq potassium, 5 mEq calcium, 3 mEq magnesium,
40 mEq chloride, 12 mEq acetate, and 12 mEq lactate. The osmolarity is 377 mOsmol/L (calc).
Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is
180 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 117
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to
carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 118
administration of lactate or acetate ions should be done with great care in those conditions in which
there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should not be administered simultaneously with blood through the same administration set
because of the likelihood of coagulation.
The intravenous administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 2, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE M and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) containing sodium or potassium
ions may result in sodium or potassium retention.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 119
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). It is also
not known whether PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE M and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 2, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 120
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 121
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) in AVIVA plastic containers is available as shown below:
Size (mL)
Code
NDC
1000
6E2564
NDC 0338-6319-04
500
6E2563
NDC 0338-6319-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 122
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 123
Baxter
PLASMA-LYTE R INJECTION (Multiple Electrolytes Injection, Type
2, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is a sterile, nonpyrogenic
isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 640
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 496 mg of Sodium Chloride, USP (NaCl);
89.6 mg of Sodium Lactate (C3H5NaO3); 74.6 mg of Potassium Chloride, USP (KCl); 36.8 mg of
Calcium Chloride, USP (CaCl2•2H2O); and 30.5 mg of Magnesium Chloride, USP (MgCl2•6H2O). It
contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to
8.0).
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) administered
intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 10 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 103 mEq
chloride, 47 mEq acetate, and 8 mEq lactate. The osmolarity is 312 mOsmol/L (calc). Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially
hypertonic solutions may cause vein damage. The caloric content is 11 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 124
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) produces a metabolic
alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water,
which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is indicated as a source of
water and electrolytes or as an alkalinizing agent.
Contraindications
None known
Warnings
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states
in which there exists edema with sodium retention.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium
retention is present.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care in patients with metabolic or respiratory alkalosis. The administration of lactate or acetate ions
should be done with great care in those conditions in which there is an increased level or an impaired
utilization of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should not be
administered simultaneously with blood through the same administration set because of the likelihood
of coagulation.
The intravenous administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type
2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE R Injection (Multiple
Electrolytes Injection, Type 2, USP) may result in sodium or potassium retention. PLASMA-LYTE R
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 125
Injection (Multiple Electrolytes Injection, Type 2, USP) is not for use in the treatment of lactic
acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE R Injection (Multiple Electrolytes
Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
R Injection (Multiple Electrolytes Injection, Type 2, USP). It is also not known whether PLASMA-
LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE R Injection
(Multiple Electrolytes Injection, Type 2, USP) should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 126
Studies have not been conducted to evaluate the effects of PLASMA-LYTE R Injection (Multiple
Electrolytes Injection, Type 2, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE R Injection (Multiple Electrolytes
Injection, Type 2, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 127
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2504
1000
NDC 0338-6320-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 128
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium
chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 129
Baxter
PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in
a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg
Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30
mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0
to 6.5). The pH is adjusted with hydrochloric acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq
chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially
hypertonic solutions (>600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 130
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized
ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and
in conditions in which potassium retention is present.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of acetate or gluconate ions should be done with great care in those conditions in which
there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 131
The intravenous administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 148 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 132
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also
not known whether PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and
well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 133
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) in AVIVA plastic containers is available as shown below:
Size (mL)
Code
NDC
1000
6E2584
NDC 0338-6321-04
500
6E2583
NDC 0338-6321-03
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 134
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 135
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 136
Baxter
5% Dextrose and Electrolyte No. 48 Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 260 mg Sodium Lactate (C3H5NaO3), 141 mg Potassium Chloride, USP (KCl), 31 mg
Magnesium Chloride, USP (MgCl2•6H20), 20 mg Monobasic Potassium Phosphate, NF (KH2PO4), and
12 mg Sodium Chloride, USP (NaCl). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 25 mEq sodium, 20 mEq potassium, 3 mEq magnesium, 24 mEq
chloride, 23 mEq lactate and 3 mEq phosphate as HPO4
=. The osmolarity is 348 mOsmol/L (calc).
Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is
180 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 137
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon
dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of lactate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 138
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should not be administered simultaneously with blood through the same administration set
because of the possibility of pseudoagglutination or hemolysis.
The intravenous administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of
solute overload causing congested states with peripheral and pulmonary edema is directly proportional
to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 48
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Do not administer simultaneously with blood.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 139
Drug Interactions
Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 48 Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5%
Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and
Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not
known whether 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 48
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when 5% Dextrose and Electrolyte No. 48 Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of dextrose and electrolytes solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemmorhage.
Geriatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 140
Clinical studies of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in the responses between elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or
drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 141
How Supplied
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2102
250
NDC 0338-6322-02
6E2103
500
NDC 0338-6322-03
6E2104
1000
NDC 0338-6322-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 142
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 143
Baxter
Potassium Chloride in 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
Composition
(g/L)
Ionic
Concentration
(mEq/L)
Table 1
Potassium Chloride in 5%
Dextrose Injection, USP
mEq Potassium
Size (mL)
**Dextrose Hydrous, USP
Potassium Chloride, USP (KCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Potassium
Chloride
Caloric Content (kcal/L)
10 mEq
1000
50
0.75
272
4.5
(3.5 to 6.5)
10
10
170
20 mEq
1000
50
1.5
293
4.5
(3.5 to 6.5)
20
20
170
30 mEq
1000
50
2.24
312
4.5
(3.5 to 6.5)
30
30
170
40 mEq
1000
20 mEq
500
50
3
333
4.5
(3.5 to 6.5)
40
40
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 144
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system. The flexible container is a closed
system, and air is prefilled in the container to facilitate drainage. The container does not require entry
of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwarp is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose Injection, USP is a source of water, electrolytes and calories. It is
capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Potassium Chloride in 5% Dextrose Injection, USP should be used with great care, if at all, in patients
with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The bag label for these injections bears the statement: Do not
administer simultaneously with blood.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 145
The intravenous administration of Potassium Chloride in 5% Dextrose Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose
Injection, USP may result in potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Potassium Chloride in 5% Dextrose Injection, USP should be used with caution in patients with overt
or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Studies have not been conducted to evaluate drug/drug or drug/food interactions with Potassium
Chloride in 5% Dextrose Injection, USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 146
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in 5%
Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Potassium Chloride in 5% Dextrose Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose
Injection, USP on labor and delivery. Caution should be exercised when administering this drug labor
and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose Injection in pediatric patients have not
been established by adequate and well-controlled studies. However, the use of potassium chloride
injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not
feasible is referenced in the medical literature.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indication and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose Injection, USP did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in the responses between
elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 147
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of a final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment of
the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Potassium Chloride in 5% Dextrose Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
Product Name
6E1124
1000
0338-6323-04
10 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1134
1000
0338-6324-04
20 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 148
6E1174
1000
0338-6325-04
30 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1264
1000
0338-6326-04
40 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1263
500
0338-6326-03
20 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 149
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 150
Baxter
Potassium Chloride in Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Potassium Chloride in Sodium Chloride Injection, USP is a sterile, nonpyrogenic, solution for fluid
and electrolyte replenishment in a single dose container for intravenous administration. It contains no
antimicrobial agents. Composition, osmolarity, pH and ionic concentration are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium
Chloride, USP
(NaCl)
Potassium
Chloride, USP
(KCl)
*Osmolarity (mOsmol/L)
(Calc.)
pH
Sodium
Potassium
Chloride
20 mEq/L Potassium Chloride in
0.9% Sodium Chloride Injection,
USP
1000
9
1.5
348
5.5
(3.5 to 6.5)
154
20
174
40 mEq/L Potassium Chloride in
0.9% Sodium Chloride Injection,
USP
1000
9
3
388
5.5
(3.5 to 6.5)
154
40
194
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 151
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in Sodium Chloride Injection, USP has value as a source of water and electrolytes.
It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Potassium Chloride in Sodium Chloride Injection, USP is indicated as a source of water and
electrolytes.
Contraindications
None known
Warnings
Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in
patients with congestive heart failure, severe renal insufficiency and in clinical states in which there
exists edema with sodium retention.
Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in
patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is
present.
The intravenous administration of Potassium Chloride in Sodium Chloride Injection, USP can cause
fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Potassium Chloride in Sodium Chloride
Injection, USP may result in sodium or potassium retention.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 152
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in Sodium Chloride Injection,
USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in Sodium Chloride Injection, USP have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in
Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. Potassium Chloride in Sodium Chloride Injection, USP should be given
to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in Sodium Chloride
Injection, USP on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in Sodium Chloride Injection, USP
is administered to a nursing mother.
Pediatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 153
Safety and effectiveness of Potassium Chloride in Sodium Chloride Injection, USP in pediatric patients
have not been established by adequate and well-controlled studies. However, the use of potassium
chloride injection in pediatric patients to treat potassium deficiency states when oral replacement
therapy is not feasible is referenced in the medical literature.
Geriatric Use
Clinical studies of Potassium Chloride in Sodium Chloride Injection, USP did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in the responses between
elderly and younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 154
Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container is available as
follows:
Code
Size (mL)
NDC
Product Name
6E1764
1000
0338-6327-04
20 mEq/L
Potassium Chloride
in 0.9% Sodium
Chloride Injection,
USP
6E1984
1000
0338-6328-04
40 mEq/L
Potassium Chloride
in 0.9% Sodium
Chloride Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25º C/77° F); brief exposure up to 40º C
(104º F) does not adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 155
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 156
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 157
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 158
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 159
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 160
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 161
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in the
responses between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Use of a final filter is recommended during administration of all parenteral solutions, where possible.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 162
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 163
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 164
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 165
Baxter
Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below.
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an
osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an
osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 166
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis
procedures.
Contraindications
None known.
Warnings
Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
In patients with diminished renal function, administration of Sodium Chloride Injection, USP may
result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 167
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride
Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in
the pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Chloride Injection, USP did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in the responses between elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 168
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
The available sizes of each injection in AVIVA plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
6E1313
500
0338-6333-03
0.45% Sodium Chloride Injection,
USP
6E1314
1000
0338-6333-04
6E1356
250
0338-6333-02
6E1322
250
0338-6304-02
0.9% Sodium Chloride Injection,
USP
6E1323
500
0338-6304-03
6E1324
1000
0338-6304-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C/77°F); brief exposure up to
40°C(104°F) does not adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 169
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
For Product Information
1-800-833-0303
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 170
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 171
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 172
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 173
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 174
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 175
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in the
responses between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Use of a final filter is recommended during administration of all parenteral solutions, where possible.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 176
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 177
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 178
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 179
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 180
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 181
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 182
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 183
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 184
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in the
responses between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Use of a final filter is recommended during administration of all parenteral solutions, where possible.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 185
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 186
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 187
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 188
Baxter
5% Dextrose and Electrolyte No. 75 Injection
(Multiple Electrolytes and Dextrose Injection, Type 3, USP)
in AVIVA Plastic Container
Description
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 220 mg Sodium Lactate (C3H5Na03), 205 mg Potassium Chloride, USP (KCl), 120 mg Sodium
Chloride, USP (NaCl), and 100 mg Monobasic Potassium Phosphate, NF (KH2PO4). It contains no
antimicrobial agents. pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 35 mEq potassium, 48 mEq chloride, 20 mEq lactate,
and 15 mEq phosphate as HPO4
=. The osmolarity is 402 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOmsol/L. Administration of substantially hypertonic
solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 189
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized in the liver to glycogen,
and ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is indicated as a source of water, electrolytes and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of lactate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes
and Dextrose Injection, Type 3, USP) can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 190
dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of
solute overloading causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 75
Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) may result in sodium or
potassium retention.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 75 Injection
(Multiple Electrolytes and Dextrose Injection, Type 3, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5%
Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 191
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and
Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). It is also not
known whether 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, USP) can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and
Dextrose Injection, Type 3, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 75
Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
IT IS NOT KNOWN WHETHER THIS DRUG IS EXCRETED IN HUMAN MILK. BECAUSE MANY DRUGS ARE EXCRETED
IN HUMAN MILK, CAUTION SHOULD BE EXERCISED WHEN 5% DEXTROSE AND ELECTROLYTE NO. 75 INJECTION
(MULTIPLE ELECTROLYTES AND DEXTROSE INJECTION, TYPE 3, USP) IS ADMINISTERED TO A NURSING
MOTHER.
Pediatric Use
Safety and effectiveness of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and
Dextrose Injection, Type 3, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of dextrose and electrolyte solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, USP) did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in the responses between elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or
drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 192
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Do not administer unless solution is clear and
seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
Additives may be incompatible. Complete information is not available.
Those additives known to be incompatible should not be used. Consult with pharmacist, if available.
If in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic
technique. Mix thoroughly when additives have been introduced. Do not store solutions containing
additives.
How Supplied
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2112
250
NDC 0338-6338-02
6E2113
500
NDC 0338-6338-03
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 193
6E2114
1000
NDC 0338-6338-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 194
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 195
Baxter
3% and 5% Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid
and electrolyte replenishment in single dose containers for intravenous administration. The pH may
have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic
concentration, osmolarity, and pH are shown in Table 1.
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
size
(mL)
Sodium Chloride
USP (NaCl)
Sodium
Chloride
*Osmolarity
(mOsmol/L)
(calc)
pH
3% Sodium
Chloride Injection,
USP
500
30
513
513
1027
5.5
(4.5 to 7.0)
5% Sodium
Chloride Injection,
USP
500
50
856
856
1711
5.5
(4.5 to 7.0)
*Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L)
may cause vein damage.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 196
Clinical Pharmacology
3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is
capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
3% and 5% Sodium Chloride Injection, USP is strongly hypertonic and may cause vein damage.
3% and 5% Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
In patients with diminished renal function, administration of 3% and 5% Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 197
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 3%
and 5% Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 3% and 5% Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 3% and 5%
Sodium Chloride Injection, USP. It is also not known whether 3% and 5% Sodium Chloride Injection,
USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
3% and 5% Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 3% and 5% Sodium Chloride Injection, USP
on labor and delivery. Caution should be exercised when administering this drug during labor and
delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when 3% and 5% Sodium Chloride Injection, USP is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not
been established by adequate and well controlled trials, however, the use of sodium chloride solutions
in the pediatric population is referenced in the medical literature. The warnings, precautions and
adverse reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of 3% and 5% Sodium Chloride Injection, USP did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 198
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of a final filter is recommended during
administration of all parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows:
Code
Size (mL)
NDC
Product Name
6E1353
500
0338-6339-03
3% Sodium
Chloride Injection,
USP
6E1373
500
0338-6340-03
5% Sodium
Chloride Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 199
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 200
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 201
Baxter
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1,
USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic,
hypotonic solution in a single dose container for intravenous administration. Each 100 mL contains
234 mg of Sodium Chloride, USP (NaCl); 128 mg of Potassium Acetate, USP (C2H3KO2); and 32 mg
of Magnesium Acetate Tetrahydrate (Mg(C2H3O2)2•4H2O). It contains no antimicrobial agents. The
pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0).
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a source of water and electrolytes. One liter has an ionic concentration of
40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The
osmolarity is 111 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310
mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage.
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 202
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic
alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which
requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of
water and electrolytes or as an alkalinizing agent.
Contraindications
None known
Warnings
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states
in which there exists edema with sodium retention.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium
retention is present.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be
done with great care in those conditions in which there is an increased level or an impaired utilization
of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should not be
administered simultaneously with blood through the same administration set because of the possibility
of hemolysis.
The intravenous administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type
1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 203
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
56 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-
LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 Injection
(Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 204
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when PLASMA-LYTE 56 Injection (Multiple Electrolytes
Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) did
not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Do not administer unless solution is clear and seal is intact.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 205
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2524
1000
NDC 0338-6341-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 206
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 207
Baxter
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown below:
Composition (g/L)
Potassium Chloride in
Lactated Ringer’s and
5% Dextrose Injection,
USP
mEq Potassium added
Size
(mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Sodium Lactate, (C3H5NaO3)
Potassium Chloride, USP
(KCl)
Calcium Chloride, USP
(CaCl2•2H2O)
*Osmolarity
(mOsmol/L) (calc.)
20 mEq
1000
50
6
3.1
1.79
0.2
565
40 mEq
1000
50
6
3.1
3.28
0.2
605
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may
cause vein damage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 208
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
Ionic Concentration
(mEq/L)
Potassium Chloride in
Lactated Ringer’s and
5% Dextrose
Injection, USP
mEq Potassium added
pH
Sodium
Potassium
Calcium
Chloride
Lactate
Caloric Content
(kcal/L)
20 mEq
5.0
(3.5 to 6.5)
130
24
3
129
28
170
40 mEq
5.0
(3.5 to 6.5)
130
44
3
149
28
170
** The chemical structure for Dextrose Hydrous, USP is shown below:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 209
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of
water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic
alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which
requires the consumption of hydrogen cations.
Indications and Usage
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of
water, electrolytes, and calories or as alkalinizing agents.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
product.
Warnings
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with metabolic or respiratory alkalosis. The administration of lactate ions
should be done with great care in those conditions in which there is an increased level or an impaired
utilization of these ions, such as severe hepatic insufficiency.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered
with blood through the same administration set because of the likelihood of coagulation.
The intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 210
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in Lactated Ringer’s
and 5% Dextrose Injection, USP may result in sodium or potassium retention.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are not for use in the
treatment of lactic acidosis.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution.
Excess administration may result in metabolic alkalosis.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer’s and 5%
Dextrose Injection, USP to patients receiving corticosteroids or corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 211
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated
Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s
and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in Lactated Ringer’s and 5%
Dextrose Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP
in pediatric patients have not been established by adequate and well controlled studies. However, the
use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose in prescribed to pediatric patients, particularly
neonates and low birth weight infants.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Geriatric Use
Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 212
from younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight, and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Use of final filter is recommended during
administration of fall parenteral solutions, where possible. Do not administer unless solution is clear
and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers
is available as shown below:
Code
Size (mL)
NDC
Product Name
6E2224
1000
NDC 0338-6344-04
20 mEq/L Potassium
Chloride in Lactated
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 213
Ringer’s and 5%
Dextrose Injection, USP
6E2244
1000
NDC 0338-6345-04
40 mEq/L Potassium
Chloride in Lactated
Ringer’s and 5%
Dextrose Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 214
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:30.411608
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/013684s092,016677s139,et al_lbl.pdf', 'application_number': 18016, 'submission_type': 'SUPPL ', 'submission_number': 57}
|
11,126
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1
INDERIDE®
(propranolol hydrochloride [Inderal®]
and hydrochlorothiazide)
Rx only
DESCRIPTION
Inderide Tablets for oral administration combine two antihypertensive agents: Inderal
(propranolol hydrochloride), a beta-adrenergic blocking agent, and hydrochlorothiazide, a
thiazide diuretic-antihypertensive. Inderide 40/25 Tablets contain 40 mg propranolol
hydrochloride and 25 mg hydrochlorothiazide; Inderide 80/25 Tablets contain 80 mg propranolol
hydrochloride and 25 mg hydrochlorothiazide.
Inderal (propranolol hydrochloride) is a synthetic beta-adrenergic receptor-blocking agent
chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-,
hydrochloride,(±)-. Its structural formula is:
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water
and ethanol. Its molecular weight is 295.80.
Hydrochlorothiazide is a white, or practically white, practically odorless, crystalline powder. It is
slightly soluble in water; freely soluble in sodium hydroxide solution; sparingly soluble in
methanol; insoluble in ether, chloroform, benzene, and dilute mineral acids. Its chemical name
is: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its structural
formula is:
The inactive ingredients contained in Inderide Tablets are lactose, magnesium stearate,
microcrystalline cellulose, stearic acid, and yellow ferric oxide.
CLINICAL PHARMACOLOGY
Propranolol hydrochloride (Inderal®)
Propranolol hydrochloride is a nonselective beta-adrenergic receptor blocking agent possessing
no other autonomic nervous system activity. It specifically competes with beta-adrenergic
receptor stimulating agents for available receptor sites. When access to beta-receptor sites is
blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic
stimulation are decreased proportionately.
Propranolol is almost completely absorbed from the gastrointestinal tract, but a portion is
immediately metabolized by the liver on its first pass through the portal circulation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Peak effect occurs in one to one-and-one-half hours. The biologic half-life is approximately four
hours. Propranolol is not significantly dialyzable. There is no simple correlation between dose or
plasma level and therapeutic effect, and the dose-sensitivity range, as observed in clinical
practice, is wide. The principal reason for this is that sympathetic tone varies widely between
individuals. Since there is no reliable test to estimate sympathetic tone or to determine whether
total beta blockade has been achieved, proper dosage requires titration.
The mechanism of the antihypertensive effect of propranolol has not been established. Among
the factors that may be involved in contributing to the antihypertensive action are (1) decreased
cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic
sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral
resistance may increase initially, it readjusts to, or below, the pretreatment level with chronic
use. Effects on plasma volume appear to be minor and somewhat variable. Propranolol has been
shown to cause a small increase in serum potassium concentration when used in the treatment of
hypertensive patients. Propranolol hydrochloride decreases heart rate, cardiac output, and blood
pressure.
Beta-receptor blockade can be useful in conditions in which, because of pathologic or functional
changes, sympathetic activity is detrimental to the patient. But there are also situations in which
sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate
ventricular function is maintained by virtue of sympathetic drive, which should be preserved. In
the presence of AV block greater than first degree, beta blockade may prevent the necessary
facilitating effect of sympathetic activity on conduction. Beta blockade results in bronchial
constriction by interfering with adrenergic bronchodilator activity, which should be preserved in
patients subject to bronchospasm.
The proper objective of beta-blockade therapy is to decrease adverse sympathetic stimulation,
but not to the degree that may impair necessary sympathetic support.
Hydrochlorothiazide
Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic closely related to chlorothiazide.
The mechanism of the antihypertensive effect of the thiazides is unknown. Thiazides do not
affect normal blood pressure.
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic
dosage, all thiazides are approximately equal in their diuretic potency.
Thiazides increase excretion of sodium and chloride in approximately equivalent amounts.
Natriuresis causes a secondary loss of potassium and bicarbonate. Onset of diuretic action of
hydrochlorothiazide occurs in two hours, and the peak effect in about four hours. Its action
persists for approximately six to 12 hours. Thiazides are eliminated rapidly by the kidney.
INDICATIONS AND USAGE
Inderide is indicated in the management of hypertension.
This fixed combination is not indicated for initial therapy of hypertension. Hypertension
requires therapy titrated to the individual patient. If the fixed combination represents the
dosage so determined, its use may be more convenient in patient management.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
CONTRAINDICATIONS
Propranolol hydrochloride (Inderal®)
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than
first-degree block; 3) bronchial asthma; 4) congestive heart failure (see “WARNINGS”) unless
the failure is secondary to a tachyarrhythmia treatable with propranolol.
Hydrochlorothiazide
Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other
sulfonamide-derived drugs.
WARNINGS
Propranolol hydrochloride (Inderal®)
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated
with the administration of propranolol (see “ADVERSE REACTIONS”).
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function
in congestive heart failure, and inhibition with beta blockade always carries the potential hazard
of further depressing myocardial contractility and precipitating cardiac failure. Propranolol acts
selectively without abolishing the inotropic action of digitalis on the heart muscle (i.e., that of
supporting the strength of myocardial contractions). In patients already receiving digitalis, the
positive inotropic action of digitalis may be reduced by propranolol's negative inotropic effect.
Patients Without a History of Heart Failure: Continued depression of the myocardium over a
period of time can, in some cases, lead to cardiac failure. In rare instances, this has been
observed during propranolol therapy. Therefore, at the first sign or symptom of impending
cardiac failure, patients should be fully digitalized and/or given additional diuretic, and the
response observed closely: a) if cardiac failure continues, despite adequate digitalization and
diuretic therapy, propranolol therapy should be withdrawn (gradually, if possible); b) if
tachyarrhythmia is being controlled, patients should be maintained on combined therapy and the
patient closely followed until threat of cardiac failure is over.
Angina Pectoris: There have been reports of exacerbation of angina and, in some cases,
myocardial infarction following abrupt discontinuation of propranolol therapy. Therefore, when
discontinuance of propranolol is planned, the dosage should be gradually reduced and the
patient should be carefully monitored. In addition, when propranolol is prescribed for angina
pectoris, the patient should be cautioned against interruption or cessation of therapy without the
physician's advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it
usually is advisable to reinstitute propranolol therapy and take other measures appropriate for
the management of unstable angina pectoris. Since coronary artery disease may be
unrecognized, it may be prudent to follow the above advice in patients considered at risk of
having occult atherosclerotic heart disease, who are given propranolol for other indications.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema): PATIENTS WITH
BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA
BLOCKERS. Propranolol should be administered with caution since it may block
bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta
receptors.
Major Surgery: The necessity or desirability of withdrawal of beta-blocking therapy prior to
major surgery is controversial. It should be noted, however, that the impaired ability of the heart
to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical
procedures.
Propranolol, like other beta blockers, is a competitive inhibitor of beta-receptor agonists, and its
effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol.
However, such patients may be subject to protracted severe hypotension. Difficulty in starting
and maintaining the heartbeat has also been reported with beta blockers.
Diabetes and Hypoglycemia: Beta-adrenergic blockade may prevent the appearance of certain
premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia in
labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage
of insulin. Hypoglycemic attack may be accompanied by a precipitous elevation of blood
pressure in patients on propranolol.
Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with
hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has
been found after this type of drug therapy and prolonged physical exertion and has occurred in
renal insufficiency, both during dialysis and sporadically, in patients on propranolol.
Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients
on propranolol.
Thyrotoxicosis: Beta blockade may mask certain clinical signs of hyperthyroidism. Therefore,
abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of
hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests,
increasing T4 and reverse T3, and decreasing T3.
Wolff-Parkinson-White Syndrome: Several cases have been reported in which, after
propranolol, the tachycardia was replaced by a severe bradycardia requiring a demand
pacemaker. In one case this resulted after an initial dose of 5 mg propranolol.
Skin Reactions: Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal
necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with
use of propranolol (see “ADVERSE REACTIONS”).
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease,
thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects
of the drug may develop.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Thiazides should also be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs
with ganglionic or peripheral adrenergic-blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma. The
possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
PRECAUTIONS
General
Propranolol hydrochloride (Inderal®)
Propranolol should be used with caution in patients with impaired hepatic or renal function.
Inderide is not indicated for the treatment of hypertensive emergencies.
Risk of anaphylactic reaction. While taking beta blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat allergic reaction.
Hydrochlorothiazide
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine
electrolyte determinations are particularly important when the patient is vomiting excessively or
receiving parenteral fluids. Medication such as digitalis may also influence serum electrolytes.
Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy,
drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria,
tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia.
Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis
(e.g., increased ventricular irritability).
Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high
potassium content.
Any chloride deficit is generally mild, and usually does not require specific treatment except
under extraordinary circumstances (as in liver or renal disease). Dilutional hyponatremia may
occur in edematous patients in hot weather; appropriate therapy is water restriction rather than
administration of salt, except in rare instances when the hyponatremia is life-threatening. In
actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
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6
Diabetes mellitus which has been latent may become manifest during thiazide administration.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic
therapy.
Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid gland with
hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged
thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis,
bone resorption, and peptic ulceration, have not been seen.
Information for Patients
Beta-adrenoreceptor blockade can cause reduction of intraocular pressure. Patients should be told
that Inderide may interfere with the glaucoma screening test. Withdrawal may lead to a return of
increased intraocular pressure.
Laboratory Tests
Propranolol hydrochloride (Inderal®)
Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase,
alkaline phosphatase, lactate dehydrogenase.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be
performed at appropriate intervals.
Drug/Drug Interactions
Propranolol hydrochloride (Inderal®)
Patients receiving catecholamine-depleting drugs such as reserpine should be closely observed if
Inderide is administered. The added catecholamine-blocking action may produce an excessive
reduction of resting sympathetic nervous activity, which may result in hypotension, marked
bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
Caution should be exercised when patients receiving a beta blocker are administered a calcium-
channel blocking drug, especially intravenous verapamil, for both agents may depress
myocardial contractility or atrioventricular conduction. On rare occasions, the concomitant
intravenous use of a beta blocker and verapamil has resulted in serious adverse reactions,
especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial
infarction.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart
rate. Concomitant use can increase the risk of bradycardia.
Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal
anti-inflammatory drugs has been reported.
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and
haloperidol.
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7
Aluminum hydroxide gel greatly reduces intestinal absorption of propranolol.
Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.
Phenytoin, phenobarbitone, and rifampin accelerate propranolol clearance.
Chlorpromazine, when used concomitantly with propranolol, results in increased plasma levels
of both drugs.
Antipyrine and lidocaine have reduced clearance when used concomitantly with propranolol.
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with
propranolol.
Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination and increasing
blood levels.
Theophylline clearance is reduced when used concomitantly with propranolol.
Hydrochlorothiazide
Thiazide drugs may increase the responsiveness to tubocurarine.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not
sufficient to preclude effectiveness of the pressor agent for therapeutic use.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Hypokalemia may develop during concomitant use of corticosteroids or ACTH.
Drug/Laboratory Test Interactions
Hydrochlorothiazide
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function (see
“PRECAUTIONS—General”).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Combinations of propranolol and hydrochlorothiazide have not been evaluated for carcinogenic
or mutagenic potential or for potential to adversely affect fertility.
Propranolol hydrochloride (Inderal®)
In dietary administration studies in which mice and rats were treated with propranolol for up to
18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis.
In a study in which both male and female rats were exposed to propranolol in their diets at
concentrations of up to 0.05%, from 60 days prior to mating and throughout pregnancy and
lactation for two generations, there were no effects on fertility. Based on differing results from
Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic
effect of propranolol in bacteria (S.typhimurium strain TA 1538).
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8
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National
Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male
and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found
equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames bacterial mutagen assay
(S.typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538) or in the Chinese
Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays
using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the
Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the
in vitro CHO Sister Chromatid Exchange (clastogenicity), Mouse Lymphoma Cell
(mutagenicity) and Aspergillus nidulans non-disjunction assays.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and
4 mg/kg, respectively, prior to mating and throughout gestation.
Pregnancy: Pregnancy Category C
Combinations of propranolol and hydrochlorothiazide have not been evaluated for effects on
pregnancy in animals. Nor are there adequate and well-controlled studies of propranolol,
hydrochlorothiazide, or Inderide in pregnant women. Inderide should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Propranolol hydrochloride (Inderal®)
In a series of reproduction and developmental toxicology studies, propranolol was given to rats
by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day
(>30 times the dose of propranolol contained in the maximum recommended human daily dose
of Inderide), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity
(reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths).
Propranolol also was administered (in the feed) to rabbits (throughout pregnancy and lactation)
at doses as high as 150 mg/kg/day (>45 times the dose of propranolol contained in the maximum
recommended daily human dose of Inderide). No evidence of embryo or neonatal toxicity was
noted.
Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported
in human neonates whose mothers received propranolol during pregnancy. Neonates whose
mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia and/or
respiratory depression. Adequate facilities for monitoring these infants at birth should be
available.
Hydrochlorothiazide
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats at doses
of up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.
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9
Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant
women requires that the anticipated benefit be weighed against possible hazards to the fetus.
These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse
reactions that have occurred in the adult.
Nursing Mothers
Propranolol hydrochloride (Inderal®)
Propranolol is excreted in human milk. Caution should be exercised when Inderide is
administered to a nursing woman.
Hydrochlorothiazide
Thiazides appear in breast milk. If the use of drug is deemed essential, the patient should stop
nursing.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Inderide did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
The following adverse reactions have been observed, but there is not enough systematic
collection of data to support an estimate of their frequency. Within each category, adverse
reactions are listed in decreasing order of severity. Although many side effects are mild and
transient, some require discontinuation of therapy.
Propranolol hydrochloride (Inderal®)
Cardiovascular: Congestive heart failure; hypotension; intensification of AV block; bradycardia;
thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type; paresthesia of
hands.
Central Nervous System: Reversible mental depression progressing to catatonia; mental
depression manifested by insomnia, lassitude, weakness, fatigue; an acute reversible syndrome
characterized by disorientation for time and place, short-term memory loss, emotional lability,
slightly clouded sensorium, decreased performance on neuropsychometrics; hallucinations;
visual disturbances; vivid dreams; light-headedness. Total daily doses above 160 mg (when
administered as divided doses of greater than 80 mg each) may be associated with an increased
incidence of fatigue, lethargy, and vivid dreams.
Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis; nausea, vomiting, epigastric
distress, abdominal cramping, diarrhea, constipation.
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10
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions;
laryngospasm and respiratory distress; pharyngitis and agranulocytosis; fever combined with
aching and sore throat; erythematous rash.
Respiratory: Bronchospasm.
Hematologic: Agranulocytosis; nonthrombocytopenic purpura; thrombocytopenic purpura.
Autoimmune: In extremely rare instances, systemic lupus erythematosus has been reported.
Miscellaneous: Male impotence. Alopecia, LE-like reactions, psoriasiform rashes, dry eyes, and
Peyronie's disease have been reported rarely. Oculomucocutaneous reactions involving the skin,
serous membranes, and conjunctivae reported for a beta blocker (practolol) have not been
associated with propranolol.
Skin: Stevens-Johnson Syndrome; toxic epidermal necrolysis; exfoliative dermatitis; erythema
multiforme; urticaria.
Hydrochlorothiazide
Cardiovascular: Orthostatic hypotension (may be aggravated by alcohol, barbiturates or
narcotics).
Central Nervous System: Dizziness, vertigo, headache, xanthopsia, paresthesias.
Gastrointestinal: Pancreatitis; jaundice (intrahepatic cholestatic jaundice); sialadenitis; anorexia,
nausea, vomiting, gastric irritation, cramping, diarrhea, constipation.
Hypersensitivity: Anaphylactic reactions; necrotizing angiitis (vasculitis, cutaneous vasculitis);
respiratory distress including pneumonitis; fever; urticaria, rash, purpura, photosensitivity.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Miscellaneous: Hyperglycemia, glycosuria; hyperuricemia; muscle spasm; weakness;
restlessness; transient blurred vision.
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or
therapy withdrawn.
OVERDOSAGE
The propranolol hydrochloride component may cause bradycardia, cardiac failure, hypotension,
or bronchospasm. Propranolol is not significantly dialyzable.
The hydrochlorothiazide component can be expected to cause diuresis. Lethargy of varying
degree may appear and may progress to coma within a few hours, with minimal depression of
respiration and cardiovascular function, and in the absence of significant serum electrolyte
changes or dehydration. The mechanism of central nervous system depression with thiazide
overdosage is unknown. Gastrointestinal irritation and hypermotility can occur, temporary
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11
elevation of BUN has been reported, and serum electrolyte changes could occur, especially in
patients with impairment of renal function.
The oral LD50 dosages in rats and mice for propranolol, hydrochlorothiazide, and combined
propranolol/hydrochlorothiazide (40/25, 80/25) are 364 to 533 mg/kg, greater than
2,750 to 5,000 mg/kg, and 538 to 845 mg/kg, respectively.
Treatment
The following measures should be employed:
General—If ingestion is, or may have been, recent, evacuate gastric contents, taking care to
prevent pulmonary aspiration.
Bradycardia—Administer atropine (0.25 to 1.0 mg). If there is no response to vagal blockade,
administer isoproterenol cautiously.
Cardiac Failure—Digitalization and diuretics.
Hypotension—Vasopressors, e.g., levarterenol or epinephrine.
Bronchospasm—Administer isoproterenol and aminophylline.
Stupor or Coma—Administer supportive therapy as clinically warranted.
Gastrointestinal Effects—Though usually of short duration, these may require symptomatic
treatment.
Abnormalities in BUN and/or Serum Electrolytes—Monitor serum electrolyte levels and renal
function; institute supportive measures as required individually to maintain hydration, electrolyte
balance, respiration, and cardiovascular-renal function.
DOSAGE AND ADMINISTRATION
The dosage must be determined by individual titration.
Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. The initial
dose of propranolol is 80 mg daily, and it may be increased gradually until optimal blood
pressure control is achieved. The usual effective dose when used alone is 160 to 480 mg per day.
One Inderide Tablet twice daily can be used to administer up to 160 mg of propranolol and
50 mg of hydrochlorothiazide. For doses of propranolol greater than 160 mg the combination
products are not appropriate, because their use would lead to an excessive dose of the thiazide
component.
When necessary, another antihypertensive agent may be added gradually beginning with
50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure.
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12
HOW SUPPLIED
Inderide 40/25
Each hexagonal-shaped, off-white, scored tablet, embossed with an “I” and imprinted with
“INDERIDE 40/25,” contains 40 mg propranolol hydrochloride (Inderal®) and 25 mg
hydrochlorothiazide, in bottles of 100 (NDC 0046-0484-81).
Inderide 80/25
Each hexagonal-shaped, off-white, scored tablet, embossed with an “I” and imprinted with
“INDERIDE 80/25,” contains 80 mg propranolol hydrochloride (Inderal®) and 25 mg
hydrochlorothiazide, in bottles of 100 (NDC 0046-0488-81).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°-30°C (59°-86°C). [See USP
Controlled Room Temperature]
Protect from moisture, freezing, and excessive heat.
Dispense in a well-closed container as defined in the USP.
The appearance of these tablets is a registered trademark of Wyeth Pharmaceuticals.
This product’s label may have been updated. For current package insert and
further product information, please visit www.wyeth.com or call our medical
communications department toll-free at 1-800-934-5556.
Wyeth®
Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
(Update W10487C005)
(Update ET01)
(Update Rev Date)
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|
custom-source
|
2025-02-12T13:44:30.504399
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018031s035lbl.pdf', 'application_number': 18031, 'submission_type': 'SUPPL ', 'submission_number': 35}
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11,125
|
Ritalin® hydrochloride
methylphenidate hydrochloride USP
tablets
Ritalin-SR®
methylphenidate hydrochloride USP
sustained-release tablets
Rx only
Prescribing Information
DESCRIPTION
Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system (CNS)
stimulant, available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as
sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl
α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is structural formula
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to
litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform
and in acetone. Its molecular weight is 269.77.
Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3
(10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets),
sucrose, talc, and tragacanth (20-mg tablets).
Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil,
povidone, titanium dioxide, and zein.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Ritalin is a mild central nervous system stimulant.
The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem
arousal system and cortex to produce its stimulant effect.
There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its
mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to
the condition of the central nervous system.
Effects on QT Interval
The effect of Focalin® XR (dexmethylphenidate, the pharmacologically active d-enantiomer of Ritalin) on
the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)-controlled
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study following single doses of Focalin XR 40 mg in 75 healthy volunteers. ECGs were collected up to 12
hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT
interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and the upper limit of
the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was
below the threshold of clinical concern and there was no evident-exposure response relationship.
Pharmacokinetics
Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative
bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of Ritalin
major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101%
(85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR tablets
and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in
children as compared to 86% in adults.
In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s
major metabolite appeared to be greater in females than in males. No gender differences were observed for
Ritalin plasma concentration in the same subjects.
INDICATIONS
Attention Deficit Disorders, Narcolepsy
Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms
being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal
Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction.
Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial
measures (psychological, educational, social) for a stabilizing effect in children with a behavioral
syndrome characterized by the following group of developmentally inappropriate symptoms:
moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity.
The diagnosis of this syndrome should not be made with finality when these symptoms are only of
comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal
EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be
warranted.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis
requires the use not only of medical but of special psychological, educational, and social resources.
Characteristics commonly reported include: chronic history of short attention span, distractibility,
emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and
abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete
history and evaluation of the child and not solely on the presence of 1 or more of these characteristics.
Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in
the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders,
including psychosis. Appropriate educational placement is essential and psychosocial intervention is
generally necessary. When remedial measures alone are insufficient, the decision to prescribe stimulant
medication will depend upon the physician’s assessment of the chronicity and severity of the child’s
symptoms.
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CONTRAINDICATIONS
Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these
symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients
with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s
syndrome.
Ritalin is contraindicated during treatment with monoamine oxidase inhibitors, and also within a
minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises
may result).
WARNINGS
Serious Cardiovascular Events
Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart
Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children
and adolescents with structural cardiac abnormalities or other serious heart problems. Although some
serious heart problems alone carry an increased risk of sudden death, stimulant products generally should
not be used in children or adolescents with known serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place
them at increased vulnerability to the sympathomimetic effects of a stimulant drug.
Adults
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at
usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a
greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy,
serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with
such abnormalities should also generally not be treated with stimulant drugs.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average
heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone
would not be expected to have short-term consequences, all patients should be monitored for larger
changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying
medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with
preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
Children, adolescents, or adults who are being considered for treatment with stimulant medications should
have a careful history (including assessment for a family history of sudden death or ventricular
arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further
cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients
who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive
of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.
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Psychiatric Adverse Events
Preexisting Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in
patients with a preexisting psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar
disorder because of concern for possible induction of a mixed/ manic episode in such patients. Prior to
initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a detailed
psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in
children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants
at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the
stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-
term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of
3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated
patients compared to 0 in placebo-treated patients.
Aggression
Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been
reported in clinical trials and the postmarketing experience of some medications indicated for the
treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior
or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or
worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either
methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups
of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10
to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout
the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height
and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of
development. Published data are inadequate to determine whether chronic use of amphetamines may cause
a similar suppression of growth, however, it is anticipated that they likely have this effect as well.
Therefore, growth should be monitored during treatment with stimulants, and patients who are not
growing or gaining height or weight as expected may need to have their treatment interrupted.
Seizures
There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior
history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in
patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures,
the drug should be discontinued.
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Priapism
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with
methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug
initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has
also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who
develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
Peripheral Vasculopathy, Including Raynaud’s Phenomenon
Stimulants, including Ritalin and Ritalin-SR, used to treat ADHD are associated with peripheral
vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild;
however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral
vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different
times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms
generally improve after reduction in dose or discontinuation of drug. Careful observation for digital
changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g.,
rheumatology referral) may be appropriate for certain patients.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Use in Children Under Six Years of Age
Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not
been established.
Drug Dependence
Ritalin should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic
abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal
behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is
required during withdrawal from abusive use, since severe depression may occur. Withdrawal following
chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.
PRECAUTIONS
Patients with an element of agitation may react adversely; discontinue therapy if necessary.
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in
light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend
on the physician’s assessment of the chronicity and severity of the child’s symptoms and their
appropriateness for his/her age. Prescription should not depend solely on the presence of 1 or more of the
behavioral characteristics.
When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not
indicated.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about
the benefits and risks associated with treatment with methylphenidate and should counsel them in its
appropriate use. A patient Medication Guide is available for Ritalin and Ritalin-SR. The prescriber or
Reference ID: 3734564
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health professional should instruct patients, their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The
complete text of the Medication Guide is reprinted at the end of this document.
Priapism
Advise patients, caregivers, and family members of the possibility of painful or prolonged penile
erections (priapism). Instruct the patient to seek immediate medical attention in the event of
priapism.
Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]
Instruct patients beginning treatment with Ritalin or Ritalin-SR about the risk of peripheral
vasculopathy, including Raynaud’s Phenomenon, and in associated signs and symptoms: fingers or
toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.
Instruct patients to report to their physician any new numbness, pain, skin color change, or
sensitivity to temperature in fingers or toes.
Instruct patients to call their physician immediately with any signs of unexplained wounds
appearing on fingers or toes while taking Ritalin or Ritalin-SR.
Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
Drug Interactions
Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with
MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible
effects on blood pressure, Ritalin should be used cautiously with pressor agents.
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is
metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways.
Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of
coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs
(e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be
required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and
monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or
discontinuing methylphenidate.
Carcinogenesis/Mutagenesis/Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in
hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of
approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum
recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare
rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain
used is sensitive to the development of hepatic tumors, and the significance of these results to humans is
unknown.
Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in
F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5
times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic
carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing
Reference ID: 3734564
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the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups
were exposed to 60-74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse
lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were
increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster
Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone
marrow micronucleus assay.
Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in
an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day,
approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis,
respectively.
PREGNANCY
Pregnancy Category C
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and
200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence
of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the
maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryofetal
development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence
of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen
at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no
effect level for embryofetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis).
When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45
mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2
basis), but no other effects on postnatal development were observed. The no effect level for pre- and
postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis).
Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised if Ritalin is administered to a nursing woman.
Pediatric Use
Ritalin should not be used in children under 6 years of age (see WARNINGS).
In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100
mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through
sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14),
decreased spontaneous locomotor activity was observed in males and females previously treated with 50
mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis)
or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the
highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral
development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the
long-term behavioral effects observed in rats is unknown.
Reference ID: 3734564
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ADVERSE REACTIONS
Nervousness and insomnia are the most common adverse reactions but are usually controlled by reducing
dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity
(including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with
histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea;
dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and
down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy;
libido changes. There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported.
Although a definite causal relationship has not been established, the following have been reported in
patients taking this drug: rhabdomyolysis, instances of abnormal liver function, ranging from transaminase
elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia;
transient depressed mood; aggressive behavior; a few instances of scalp hair loss. Very rare reports of
neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were
concurrently receiving therapies associated with NMS. In a single report, a 10-year-old boy who had been
taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes
of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug
interaction, a response to either drug alone, or some other cause.
In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and
tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also
occur.
DOSAGE AND ADMINISTRATION
Dosage should be individualized according to the needs and responses of the patient.
Adults
Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals.
Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg
daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take
the last dose before 6 p.m.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR
tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the
titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or
chewed.
Children (6 years and over)
Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is
not recommended.
If improvement is not observed after appropriate dosage adjustment over a 1-month period, the drug
should be discontinued.
Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg
weekly.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR
tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the
titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or
chewed.
Reference ID: 3734564
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If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary,
discontinue the drug.
Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained
when the drug is either temporarily or permanently discontinued.
Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.
OVERDOSAGE
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central
nervous system and from excessive sympathomimetic effects, may include the following: vomiting,
agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria,
confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations,
cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Rhabdomyolysis has
also been reported in overdose.
Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.
Treatment consists of appropriate supportive measures. The patient must be protected against self-injury
and against external stimuli that would aggravate overstimulation already present. Gastric contents may be
evacuated by gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of a
short-acting barbiturate before performing gastric lavage. Other measures to detoxify the gut include
administration of activated charcoal and a cathartic.
Intensive care must be provided to maintain adequate circulation and respiratory exchange; external
cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been
established.
HOW SUPPLIED
Tablets 5 mg-round, yellow (imprinted CIBA 7)
Bottles of 100 ...............................................……………………………......NDC 0078-0439-05
Tablets 10 mg-round, pale green, scored (imprinted CIBA 3)
Bottles of 100 .................................................................................................NDC 0078-0440-05
Tablets 20 mg-round, pale yellow, scored (imprinted CIBA 34)
Bottles of 100 .......………………………………………………………......NDC 0078-0441-05
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room
Temperature]. Protect from light.
Dispense in tight, light-resistant container (USP).
SR Tablets 20 mg-round, white, coated (imprinted CIBA 16)
Bottles of 100……………………………………………………………...NDC 0078-0442-05
Note: SR Tablets are color-additive free.
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room
Temperature]. Protect from moisture.
Dispense in tight, light-resistant container (USP).
Reference ID: 3734564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
T2015-XX
Month Year
Reference ID: 3734564
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MEDICATION GUIDE
RITALIN®
(methylphenidate hydrochloride, USP) tablets CII
Read the Medication Guide that comes with RITALIN before you or your child starts taking it and each time you get
a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor
about your or your child’s treatment with RITALIN.
What is the most important information I should know about RITALIN?
The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines.
1. Heart-related problems:
sudden death in patients who have heart problems or heart defects
stroke and heart attack in adults
increased blood pressure and heart rate
Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history
of these problems.
Your doctor should check you or your child carefully for heart problems before starting RITALIN.
Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with
RITALIN.
Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness
of breath, or fainting while taking RITALIN.
2. Mental (Psychiatric) problems:
All Patients
new or worse behavior and thought problems
new or worse bipolar illness
new or worse aggressive behavior or hostility
Children and Teenagers
new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new
manic symptoms
Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar
illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems
while taking RITALIN, especially seeing or hearing things that are not real, believing things that are not real,
or are suspicious.
3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers
or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red
Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in
the fingers or toes.
Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on
fingers or toes while taking RITALIN.
What Is RITALIN?
RITALIN is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-
Deficit Hyperactivity Disorder (ADHD). RITALIN may help increase attention and decrease impulsiveness and
hyperactivity in patients with ADHD.
Reference ID: 3734564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
RITALIN should be used as a part of a total treatment program for ADHD that may include counseling or other
therapies.
RITALIN is also used in the treatment of a sleep disorder called narcolepsy.
RITALIN is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep
RITALIN in a safe place to prevent misuse and abuse. Selling or giving away RITALIN may harm others,
and is against the law.
Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol,
prescription medicines or street drugs.
Who should not take RITALIN?
RITALIN should not be taken if you or your child:
are very anxious, tense, or agitated
have an eye problem called glaucoma
have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated
movements or sounds.
are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase
inhibitor or MAOI.
are allergic to anything in RITALIN. See the end of this Medication Guide for a complete list of ingredients.
RITALIN should not be used in children less than 6 years old because it has not been studied in this age group.
RITALIN may not be right for you or your child. Before starting RITALIN tell your or your child’s doctor
about all health conditions (or a family history of) including:
heart problems, heart defects, high blood pressure
mental problems including psychosis, mania, bipolar illness, or depression
tics or Tourette’s syndrome
seizures or have had an abnormal brain wave test (EEG)
circulation problems in fingers or toes
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.
Can RITALIN be taken with other medicines?
Tell your doctor about all of the medicines that you or your child takes including prescription and
nonprescription medicines, vitamins, and herbal supplements. RITALIN and some medicines may interact with
each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while
taking RITALIN.
Your doctor will decide whether RITALIN can be taken with other medicines.
Especially tell your doctor if you or your child takes:
anti-depression medicines including MAOIs
seizure medicines
blood thinner medicines
blood pressure medicines
cold or allergy medicines that contain decongestants
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and
pharmacist.
Do not start any new medicine while taking RITALIN without talking to your doctor first.
How should RITALIN be taken?
Take RITALIN exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.
RITALIN is usually taken 2 to 3 times a day.
Take RITALIN 30 to 45 minutes before a meal.
Reference ID: 3734564
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From time to time, your doctor may stop RITALIN treatment for a while to check ADHD symptoms.
Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN. Children
should have their height and weight checked often while taking RITALIN. RITALIN treatment may be stopped
if a problem is found during these check-ups.
If you or your child takes too much RITALIN or overdoses, call your doctor or poison control center
right away, or get emergency treatment.
What are possible side effects of RITALIN?
See “What is the most important information I should know about RITALIN?” for information on reported
heart and mental problems.
Other serious side effects include:
slowing of growth (height and weight) in children
seizures, mainly in patients with a history of seizures
eyesight changes or blurred vision
painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop
priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be
evaluated by a doctor immediately.
Common side effects include:
headache
• decreased appetite
stomach ache
• nervousness
trouble sleeping
nausea
Talk to your doctor if you or your child has side effects that are bothersome or do not go away.
This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.
How should I store RITALIN?
Store RITALIN in a safe place at room temperature, 59°F to 86°F (15°C to 30°C). Protect from light.
Keep RITALIN and all medicines out of the reach of children.
General information about RITALIN.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
RITALIN for a condition for which it was not prescribed. Do not give RITALIN to other people, even if they have
the same condition. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about RITALIN. If you would like more
information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN that was
written for healthcare professionals. For more information about RITALIN call 1-888-669-6682.
What are the ingredients in RITALIN?
Active Ingredient: methylphenidate HCL
Inactive Ingredients: D&C Yellow No.10 (5-mg and 20-mg tablets), FD&C Green No.3 (10-mg tablets), lactose,
magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg
tablets).
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
T2013-126
December 2013
Reference ID: 3734564
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For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
RITALIN-SR®
(methylphenidate hydrochloride, USP) sustained-release tablets CII
Read the Medication Guide that comes with RITALIN-SR before you or your child starts taking it and each time you
get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor
about your or your child’s treatment with RITALIN-SR.
What is the most important information I should know about RITALIN-SR?
The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines.
1. Heart-related problems:
sudden death in patients who have heart problems or heart defects
stroke and heart attack in adults
increased blood pressure and heart rate
Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history
of these problems.
Your doctor should check you or your child carefully for heart problems before starting RITALIN-SR.
Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with
RITALIN-SR.
Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness
of breath, or fainting while taking RITALIN-SR.
2. Mental (Psychiatric) problems:
All Patients
new or worse behavior and thought problems
new or worse bipolar illness
new or worse aggressive behavior or hostility
Children and Teenagers
new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new
manic symptoms
Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar
illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems
while taking RITALIN-SR, especially seeing or hearing things that are not real, believing things that are not
real, or are suspicious.
3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]: fingers
or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red
Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in
the fingers or toes.
Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on
fingers or toes while taking RITALIN-SR.
Reference ID: 3734564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What Is RITALIN-SR?
RITALIN-SR is a central nervous system stimulant prescription medicine. It is used for the treatment of
Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN-SR may help increase attention and decrease
impulsiveness and hyperactivity in patients with ADHD.
RITALIN-SR should be used as a part of a total treatment program for ADHD that may include counseling or other
therapies.
RITALIN-SR is also used in the treatment of a sleep disorder called narcolepsy.
RITALIN-SR is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep
RITALIN-SR in a safe place to prevent misuse and abuse. Selling or giving away RITALIN-SR may harm
others, and is against the law.
Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol,
prescription medicines or street drugs.
Who should not take RITALIN-SR?
RITALIN-SR should not be taken if you or your child:
are very anxious, tense, or agitated
have an eye problem called glaucoma
have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to control repeated
movements or sounds.
are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase
inhibitor or MAOI.
are allergic to anything in RITALIN-SR. See the end of this Medication Guide for a complete list of ingredients.
RITALIN-SR should not be used in children less than 6 years old because it has not been studied in this age group.
RITALIN-SR may not be right for you or your child. Before starting RITALIN-SR tell your or your child’s
doctor about all health conditions (or a family history of) including:
heart problems, heart defects, high blood pressure
mental problems including psychosis, mania, bipolar illness, or depression
tics or Tourette’s syndrome
seizures or have had an abnormal brain wave test (EEG)
circulation problems in fingers or toes
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.
Can RITALIN-SR be taken with other medicines?
Tell your doctor about all of the medicines that you or your child takes including prescription and
nonprescription medicines, vitamins, and herbal supplements. RITALIN-SR and some medicines may interact
with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted
while taking RITALIN-SR.
Your doctor will decide whether RITALIN-SR can be taken with other medicines.
Especially tell your doctor if you or your child takes:
anti-depression medicines including MAOIs
seizure medicines
blood thinner medicines
blood pressure medicines
cold or allergy medicines that contain decongestants
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and
pharmacist.
Do not start any new medicine while taking RITALIN-SR without talking to your doctor first.
Reference ID: 3734564
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should RITALIN-SR be taken?
Take RITALIN-SR exactly as prescribed. Your doctor may adjust the dose until it is right for you or your
child.
Take RITALIN-SR 30 to 45 minutes before a meal. The effect of a dose of RITALIN-SR usually lasts about 8
hours.
Do not chew or crush RITALIN-SR tablets. Swallow RITALIN-SR tablets whole with water or other liquids.
Tell your doctor if you or your child cannot swallow RITALIN-SR whole. A different medicine may need to be
prescribed.
From time to time, your doctor may stop RITALIN-SR treatment for a while to check ADHD symptoms.
Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN-SR. Children
should have their height and weight checked often while taking RITALIN-SR. RITALIN-SR treatment may be
stopped if a problem is found during these check-ups.
If you or your child takes too much RITALIN-SR or overdoses, call your doctor or poison control center
right away, or get emergency treatment.
What are possible side effects of RITALIN-SR?
See “What is the most important information I should know about RITALIN-SR?” for information on reported
heart and mental problems.
Other serious side effects include:
slowing of growth (height and weight) in children
seizures, mainly in patients with a history of seizures
eyesight changes or blurred vision
painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop
priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be
evaluated by a doctor immediately.
Common side effects include:
headache
• decreased appetite
stomach ache
• nervousness
trouble sleeping
nausea
Talk to your doctor if you or your child has side effects that are bothersome or do not go away.
This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.
How should I store RITALIN-SR?
Store RITALIN-SR in a safe place at room temperature, 59°F to 86°F (15°C to 30°C). Protect from moisture.
Keep RITALIN-SR and all medicines out of the reach of children.
General information about RITALIN-SR.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
RITALIN-SR for a condition for which it was not prescribed. Do not give RITALIN-SR to other people, even if they
have the same condition. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about RITALIN-SR. If you would like more
information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN-SR that
was written for healthcare professionals. For more information about RITALIN-SR call 1-888-669-6682.
What are the ingredients in RITALIN-SR?
Active Ingredient: methylphenidate HCL, USP
Inactive Ingredients: cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone,
titanium dioxide, and zein
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Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2015-XX/T2013-126/T2013-127
Month Year/December 2013/December 2013
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Ritalin LA®
(methylphenidate hydrochloride)
extended-release capsules
Rx only
Prescribing Information
DESCRIPTION
Methylphenidate hydrochloride is a central nervous system (CNS) stimulant.
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is an extended-release
formulation of methylphenidate with a bi-modal release profile. Ritalin LA uses the proprietary
SODAS® (Spheroidal Oral Drug Absorption System) technology. Each bead-filled Ritalin LA capsule
contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads,
thus providing an immediate release of methylphenidate and a second delayed release of
methylphenidate. Ritalin LA 10, 20, 30, 40, and 60 mg capsules provide in a single dose the same
amount of methylphenidate as dosages of 5, 10, 15, 20, or 30 mg of Ritalin tablets given b.i.d.
The active substance in Ritalin LA is methyl α-phenyl-2-piperidineacetate hydrochloride, and its
structural formula is structural formula
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid
to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in
chloroform and in acetone. Its molecular weight is 269.77.
Inactive ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules
only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules
only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg
capsules only).
CLINICAL PHARMACOLOGY
Pharmacodynamics
Methylphenidate hydrochloride, the active ingredient in Ritalin LA (methylphenidate hydrochloride)
extended-release capsules, is a central nervous system (CNS) stimulant. The mode of therapeutic action
in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to
block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the
release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture
comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active
than the l-threo enantiomer.
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Effects on QT Interval
The effect of Focalin XR (dexmethylphenidate, the pharmacologically active d-enantiomer of Ritalin)
on the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)
controlled study following single doses of Focalin XR 40 mg in 75 healthy volunteers. ECGs were
collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive
the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and
the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons
versus placebo. This was below the threshold of clinical concern and there was no evident-exposure
response relationship.
Pharmacokinetics
Absorption
Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately
4 hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The
initial rate of absorption for Ritalin LA is similar to that of Ritalin tablets as shown by the similar rate
parameters between the 2 formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and
time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum
(Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA given once daily and Ritalin
tablets given in 2 doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are
greater for Ritalin LA.
Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak
minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in 2
doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the
delayed-release beads (see Figure 1 and Table 1).
The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of
Ritalin tablets given in 2 doses 4 hours apart in both children and in adults.
Figure 1. Mean Plasma Concentration Time-Profile of Methylphenidate After a Single Dose of
Ritalin LA 40 mg q.d. and Ritalin 20 mg Given in Two Doses Four Hours Apart graph
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Table 1. Mean ± SD and Range of Pharmacokinetic Parameters of Methylphenidate After a
Single Dose of Ritalin LA and Ritalin Given in Two Doses 4 Hours Apart
Population
Children
Adult Males
Formulation
Ritalin
Ritalin LA
Ritalin
Ritalin LA
Dose
10 mg & 10 mg
20 mg
10 mg & 10 mg
20 mg
N
21
18
9
8
Tlag (h)
0.24 ± 0.44
0.28 ± 0.46
1.0 ± 0.5
0.7 ± 0.2
0 - 1
0 - 1
0.7 - 1.3
0.3 - 1.0
Tmax1 (h)
1.8 ± 0.6
2.0 ± 0.8
1.9 ± 0.4
2.0 ± 0.9
1 - 3
1 - 3
1.3 - 2.7
1.3 - 4.0
Cmax1 (ng/mL)
10.2 ± 4.2
10.3 ± 5.1
4.3 ± 2.3
5.3 ± 0.9
4.2 - 20.2
5.5 - 26.6
1.8 - 7.5
3.8 - 6.9
Tminip (h)
4.0 ± 0.2
4.5 ± 1.2
3.8 ± 0.4
3.6 ± 0.6
4 - 5
2 - 6
3.3 - 4.3
2.7 - 4.3
Cminip (ng/mL)
5.8 ± 2.7
6.1 ± 4.1
1.2 ± 1.4
3.0 ± 0.8
3.1 - 14.4
2.9 - 21.0
0.0 - 3.7
1.7 - 4.0
Tmax2 (h)
5.6 ± 0.7
6.6 ± 1.5
5.9 ± 0.5
5.5 ± 0.8
5 - 8
5 - 11
5.0 - 6.5
4.3 - 6.5
Cmax2 (ng/mL)
15.3 ± 7.0
10.2 ± 5.9
5.3 ± 1.4
6.2 ± 1.6
6.2 - 32.8
4.5 - 31.1
3.6 - 7.2
3.9 - 8.3
AUC(0-∞)
102.4 ± 54.6
86.6 ± 64.0a
37.8 ± 21.9
45.8 ± 10.0
(ng/mL x h-1)
40.5 - 261.6
43.3 - 301.44
14.3 - 85.3
34.0 - 61.6
t1/2 (h)
2.5 ± 0.8
2.4 ± 0.7a
3.5 ± 1.9
3.3 ± 0.4
1.8 - 5.3
1.5 - 4.0
1.3 - 7.7
3.0 - 4.2
a N=15
Dose Proportionality
After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward
trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and
Cmax2).
Distribution
Binding to plasma proteins is low (10%-33%). The volume of distribution was 2.65±1.11 L/kg for d
methylphenidate and 1.80±0.91 L/kg for l-methylphenidate.
Metabolism
The absolute oral bioavailability of methylphenidate in children was 22±8% for d-methylphenidate and
5±3% for l-methylphenidate, suggesting pronounced presystemic metabolism. Biotransformation of
methylphenidate by the carboxylesterase CES1A1 is rapid and extensive leading to the main, de
esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid). Only small amounts of
hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in
plasma. Therapeutic activity is principally due to the parent compound.
Elimination
In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is
eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3-7.7 hours). In children
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the average half-life is about 2.5 hours, with a range of about 1.5-5.0 hours. The rapid half-life in both
children and adults may result in unmeasurable concentrations between the morning and mid-day doses
with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day
oral dosing with Ritalin LA. The half-life of ritalinic acid is about 3-4 hours.
The systemic clearance is 0.40±0.12 L/h/kg for d-methylphenidate and 0.73±0.28 L/h/kg for l
methylphenidate. After oral administration of an immediate release formulation of methylphenidate,
78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within
48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of
the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by
minor metabolites.
Food Effects
Administration times relative to meals and meal composition may need to be individually titrated.
When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had a longer lag time
until absorption began and variable delays in the time until the first peak concentration, the time until
the interpeak minimum, and the time until the second peak. The first peak concentration and the extent
of absorption were unchanged after food relative to the fasting state, although the second peak was
approximately 25% lower. The effect of a high fat lunch was not examined.
There were no differences in the pharmacokinetics of Ritalin LA when administered with applesauce,
compared to administration in the fasting condition. There is no evidence of dose dumping in the
presence or absence of food.
For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and
administered (see DOSAGE AND ADMINISTRATION).
Alcohol Effect
Alcohol may exacerbate the adverse CNS effects of psychoactive drugs, including Ritalin. It is
therefore advisable for patients to abstain from alcohol during treatment. An in vitro study was
conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the
Ritalin LA 40 mg capsule dosage form. At an alcohol concentration of 40% there was a 98% release of
methylphenidate in the first hour. The results with the 40 mg capsule are considered to be
representative of the other available capsule strengths.
Special Populations
Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between 7 and 12
years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between
peak minimum, and the time until the second peak were delayed and more variable in children
compared to adults. After a 20-mg dose of Ritalin LA, concentrations in children were approximately
twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost
completely due to the smaller body size and total volume of distribution in children, as apparent
clearance normalized to body weight is independent of age.
Gender: There were no apparent gender differences in the pharmacokinetics of methylphenidate
between healthy male and female adults when administered Ritalin LA.
Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal insufficiency
is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a
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radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic
acid), has little or no pharmacologic activity.
Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency. Hepatic
insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is
metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely
distributed throughout the body.
CLINICAL STUDIES
Ritalin LA (methylphenidate hydrochloride) extended-release capsules was evaluated in a randomized,
double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages 6 to 12, with
DSM-IV diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) received a single morning
dose of Ritalin LA in the range of 10-40 mg/day, or placebo, for up to 2 weeks. The doses used were
the optimal doses established in a previous individual dose titration phase. In that titration phase, 53 of
164 patients (32%) started on a daily dose of 10 mg and 111 of 164 patients (68%) started on a daily
dose of 20 mg or higher. The patient’s regular schoolteacher completed the Conners ADHD/DSM-IV
Scale for Teachers (CADS-T) at baseline and the end of each week. The CADS-T assesses symptoms
of hyperactivity and inattention. The change from baseline of the (CADS-T) scores during the last
week of treatment was analyzed as the primary efficacy parameter. Patients treated with Ritalin LA
showed a statistically significant improvement in symptom scores from baseline over patients who
received placebo. (See Figure 2.) This demonstrates that a single morning dose of Ritalin LA exerts a
treatment effect in ADHD.
Figure 2. CADS-T Total Subscale-Mean Change from Baseline* graph
INDICATIONS AND USAGE
Ritalin LA (methylphenidate hydrochloride) extended-release capsules is indicated for the treatment of
Attention Deficit Hyperactivity Disorder (ADHD).
The efficacy of Ritalin LA in the treatment of ADHD was established in 1 controlled trial of children
aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY).
A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of
hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7
years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or
occupational functioning, and be present in 2 or more settings, e.g., school (or work) and at home. The
symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at
least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to
details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks;
poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted;
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forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have
persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing;
difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn;
intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate
diagnosis requires the use not only of medical but of special psychological, educational, and social
resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history
and evaluation of the child and not solely on the presence of the required number of DSM-IV
characteristics.
Need for Comprehensive Treatment Program
Ritalin LA is indicated as an integral part of a total treatment program for ADHD that may include
other measures (psychological, educational, social) for patients with this syndrome. Drug treatment
may not be indicated for all children with this syndrome. Stimulants are not intended for use in the
child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric
disorders, including psychosis. Appropriate educational placement is essential and psychosocial
intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe
stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the
child’s symptoms.
Long-Term Use
The effectiveness of Ritalin LA for long-term use, i.e., for more than 2 weeks, has not been
systematically evaluated in controlled trials. Therefore, the physician who elects to use Ritalin LA for
extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual
patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Agitation
Ritalin LA (methylphenidate hydrochloride) extended-release capsules are contraindicated in marked
anxiety, tension, and agitation, since the drug may aggravate these symptoms.
Hypersensitivity to Methylphenidate
Ritalin LA is contraindicated in patients known to be hypersensitive to methylphenidate or other
components of the product.
Glaucoma
Ritalin LA is contraindicated in patients with glaucoma.
Tics
Ritalin LA is contraindicated in patients with motor tics or with a family history or diagnosis of
Tourette’s syndrome (see ADVERSE REACTIONS).
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Monoamine Oxidase Inhibitors
Ritalin LA is contraindicated during treatment with monoamine oxidase inhibitors, and also within a
minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor
(hypertensive crises may result).
WARNINGS
Serious Cardiovascular Events
Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children
and adolescents with structural cardiac abnormalities or other serious heart problems. Although some
serious heart problems alone carry an increased risk of sudden death, stimulant products generally
should not be used in children or adolescents with known serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place
them at increased vulnerability to the sympathomimetic effects of a stimulant drug.
Adults
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at
usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults
have a greater likelihood than children of having serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac
problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and
average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes
alone would not be expected to have short-term consequences, all patients should be monitored for
larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose
underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g.,
those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular
arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
Children, adolescents, or adults who are being considered for treatment with stimulant medications
should have a careful history (including assessment for a family history of sudden death or ventricular
arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further
cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram).
Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other
symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac
evaluation.
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Psychiatric Adverse Events
Preexisting Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder
in patients with a preexisting psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar
disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to
initiating treatment with a stimulant, patients with comorbid depressive symptoms should be
adequately screened to determine if they are at risk for bipolar disorder; such screening should include
a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania
in children and adolescents without a prior history of psychotic illness or mania can be caused by
stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal
role of the stimulant, and discontinuation of treatment may be appropriate.
In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in
about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for
several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.
Aggression
Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has
been reported in clinical trials and the postmarketing experience of some medications indicated for the
treatment of ADHD including methylphenidate. Although there is no systematic evidence that
stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be
monitored for the appearance of or worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either
methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic
subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to
the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per
week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm
less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth
rebound during this period of development. In the double-blind placebo-controlled study of Ritalin LA
(methylphenidate hydrochloride) extended-release capsules, the mean weight gain was greater for
patients receiving placebo (+1.0 kg) than for patients receiving Ritalin LA (+0.1 kg). Published data are
inadequate to determine whether chronic use of amphetamines may cause a similar suppression of
growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be
monitored during treatment with stimulants, and patients who are not growing or gaining height or
weight as expected may need to have their treatment interrupted.
Seizures
There is some clinical evidence that stimulants may lower the convulsive threshold in patients with
prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very
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rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence
of seizures, the drug should be discontinued.
Priapism
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with
methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug
initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism
has also appeared during a period of drug withdrawal (drug holidays or during discontinuation).
Patients who develop abnormally sustained or frequent and painful erections should seek immediate
medical attention.
Peripheral Vasculopathy, Including Raynaud’s Phenomenon
Stimulants, including Ritalin LA, used to treat ADHD are associated with peripheral vasculopathy,
including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however,
very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral
vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different
times and at therapeutic doses in all age groups throughout the course of treatment. Signs and
symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for
digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g.,
rheumatology referral) may be appropriate for certain patients.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Use in Children Under Six Years of Age
Ritalin LA should not be used in children under 6 years of age, since safety and efficacy in this age
group have not been established.
Drug Dependence
Ritalin LA should be given cautiously to patients with a history of drug dependence or alcoholism.
Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees
of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful
supervision is required during withdrawal from abusive use, since severe depression may occur.
Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that
may require follow-up.
PRECAUTIONS
Hematologic Monitoring
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with methylphenidate and should counsel them
in its appropriate use. A patient Medication Guide is available for Ritalin LA. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication Guide
and should assist them in understanding its contents. Patients should be given the opportunity to
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discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised to avoid alcohol while taking Ritalin LA. Consumption of alcohol while
taking Ritalin LA may result in a more rapid release of the dose of methylphenidate.
Priapism
Advise patients, caregivers, and family members of the possibility of painful or prolonged
penile erections (priapism). Instruct the patient to seek immediate medical attention in the
event of priapism.
Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]
Instruct patients beginning treatment with Ritalin LA about the risk of peripheral vasculopathy,
including Raynaud’s Phenomenon, and in associated signs and symptoms: fingers or toes may
feel numb, cool, painful, and/or may change color from pale, to blue, to red.
Instruct patients to report to their physician any new numbness, pain, skin color change, or
sensitivity to temperature in fingers or toes.
Instruct patients to call their physician immediately with any signs of unexplained
wounds appearing on fingers or toes while taking Ritalin LA.
Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
Drug Interactions
Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic esterases) to
ritalinic acid and not through oxidative pathways.
The effects of gastrointestinal pH alterations on the absorption of methylphenidate from Ritalin LA
have not been studied. Since the modified release characteristics of Ritalin LA are pH dependent, the
coadministration of antacids or acid suppressants could alter the release of methylphenidate.
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Because of
possible effects on blood pressure, methylphenidate should be used cautiously with pressor agents.
As an inhibitor of dopamine reuptake, methylphenidate may be associated with pharmacodynamic
interactions when coadministered with direct and indirect dopamine agonists (including DOPA and
tricyclic antidepressants) as well as dopamine antagonists (antipsychotics, e.g., haloperidol).
Case reports suggest a potential interaction of methylphenidate with coumarin anticoagulants,
anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine,
clomipramine, desipramine) but pharmacokinetic interactions were not confirmed when explored at
higher sample sizes. Downward dose adjustment of these drugs may be required when given
concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug
concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing
concomitant methylphenidate.
Methylphenidate is not metabolized by cytochrome P450 to a clinically relevant extent. Inducers or
inhibitors of cytochrome P450 are not expected to have any relevant impact on methylphenidate
pharmacokinetics. Conversely, the d- and l-enantiomers of methylphenidate did not relevantly inhibit
cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.
Methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate
desipramine.
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An interaction with the anticoagulant ethylbiscoumacetate in 4 subjects was not confirmed in a
subsequent study with a higher sample size (n=12).
Other specific drug-drug interaction studies with methylphenidate have not been performed in vivo.
Carcinogenesis/Mutagenesis/Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in
hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of
approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum
recommended human dose on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively
rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse
strain used is sensitive to the development of hepatic tumors, and the significance of these results to
humans is unknown.
Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in
F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times
and 5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to
genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets
containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the
high-dose groups were exposed to 60-74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro
mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome
aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured
Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in
the mouse bone marrow micronucleus assay.
Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug
in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day,
approximately 80-fold and 8-fold the highest recommended dose on a mg/kg and mg/m2 basis,
respectively.
Pregnancy
Pregnancy Category C
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75
and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased
incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40
times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for
embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There
was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal
variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also
maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times
the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy
and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest
dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were
observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the
MRHD on a mg/m2 basis).
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Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin LA should
be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised if Ritalin LA is administered to a nursing woman.
Pediatric Use
Long-term effects of methylphenidate in children have not been well established. Ritalin LA should not
be used in children under 6 years of age (see WARNINGS).
In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100
mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through
sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13
14), decreased spontaneous locomotor activity was observed in males and females previously treated
with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a
mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females
exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile
neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical
significance of the long-term behavioral effects observed in rats is unknown.
ADVERSE REACTIONS
The clinical program for Ritalin LA (methylphenidate hydrochloride) extended-release capsules
consisted of 6 studies: 2 controlled clinical studies conducted in children with ADHD aged 6-12 years
and 4 clinical pharmacology studies conducted in healthy adult volunteers. These studies included a
total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received
Ritalin LA in doses of 10-40 mg per day. Safety of Ritalin LA was assessed by evaluating frequency
and nature of adverse events, routine laboratory tests, vital signs, and body weight.
Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical
investigators using terminology of their own choosing. Consequently, it is not possible to provide a
meaningful estimate of the proportion of individuals experiencing adverse events without first
grouping similar types of events into a smaller number of standardized event categories. In the tables
and listings that follow, MedDRA terminology has been used to classify reported adverse events. The
stated frequencies of adverse events represent the proportion of individuals who experienced, at least
once, a treatment-emergent adverse event of the type listed. An event was considered treatment
emergent if it occurred for the first time or worsened while receiving therapy following baseline
evaluation.
Adverse Events in a Double-Blind, Placebo-Controlled, Clinical Trial with Ritalin LA
Treatment-Emergent Adverse Events
A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and
safety of Ritalin LA in children with ADHD aged 6-12 years. All subjects received Ritalin LA for up to
4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In
the 2-week, double-blind treatment phase of this study, patients received either placebo or Ritalin LA
at their individually-titrated dose (range 10 mg-40 mg).
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The prescriber should be aware that these figures cannot be used to predict the incidence of adverse
events in the course of usual medical practice where patient characteristics and other factors differ from
those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with
figures obtained from other clinical investigations involving different treatments, uses, and
investigators. The cited figures, however, do provide the prescribing physician with some basis for
estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in
the population studied.
Adverse events with an incidence >5% during the initial 4-week, single-blind Ritalin LA titration
period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.
Treatment-emergent adverse events with an incidence >2% among Ritalin LA-treated subjects, during
the 2-week, double-blind phase of the clinical study, were as follows:
Preferred term
Ritalin LA
Placebo
N=65
N=71
N (%)
N (%)
Anorexia
2 (3.1)
0 (0.0)
Insomnia
2 (3.1)
0 (0.0)
Adverse Events Associated with Discontinuation of Treatment
In the 2-week, double-blind treatment phase of a placebo-controlled parallel-group study in children
with ADHD, only 1 Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an adverse event
(depression).
In the single-blind titration period of this study, subjects received Ritalin LA for up to 4 weeks. During
this period a total of 6 subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events
leading to discontinuation were anger (in 2 patients), hypomania, anxiety, depressed mood, fatigue,
migraine and lethargy.
Adverse Events with Other Methylphenidate HCl Dosage Forms
Nervousness and insomnia are the most common adverse reactions reported with other
methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged
therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse
reactions listed below may also occur.
Other reactions include:
Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia
Gastrointestinal: abdominal pain, nausea
Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative
dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and
thrombocytopenic purpura.
Metabolism/Nutrition: anorexia, weight loss during prolonged therapy
Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome,
toxic psychosis
Vascular: blood pressure increased or decreased; cerebrovascular vasculitis; cerebral occlusions;
cerebral hemorrhages and cerebrovascular accidents
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Although a definite causal relationship has not been established, the following have been reported in
patients taking methylphenidate:
Blood/Lymphatic: leukopenia and/or anemia
Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma
Musculoskeletal: rhabdomyolysis
Psychiatric: transient depressed mood, aggressive behavior, libido changes
Skin/Subcutaneous: scalp hair loss
Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these,
patients were concurrently receiving therapies associated with NMS. In a single report, a 10-year-old
boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like
event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case
represented a drug-drug interaction, a response to either drug alone, or some other cause.
DRUG ABUSE AND DEPENDENCE
Ritalin LA (methylphenidate hydrochloride) extended-release capsules, like other products containing
methylphenidate, is a Schedule II controlled substance. (See WARNINGS for boxed warning
containing drug abuse and dependence information.)
OVERDOSAGE
Signs and Symptoms
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central
nervous system and from excessive sympathomimetic effects, may include the following: vomiting,
agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria,
confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia,
palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Rhabdomyolysis has also been reported in overdose.
Poison Control Center
Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.
Recommended Treatment
As with the management of all overdosage, the possibility of multiple drug ingestion should be
considered.
When treating overdose, practitioners should bear in mind that there is a prolonged release of
methylphenidate from Ritalin LA (methylphenidate hydrochloride) extended-release capsules.
Treatment consists of appropriate supportive measures. The patient must be protected against self-
injury and against external stimuli that would aggravate overstimulation already present. Gastric
contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control
agitation and seizures if present and protect the airway. Other measures to detoxify the gut include
administration of activated charcoal and a cathartic. Intensive care must be provided to maintain
adequate circulation and respiratory exchange; external cooling procedures may be required for
hyperpyrexia.
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Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not
been established; also, dialysis is considered unlikely to be of benefit due to the large volume of
distribution of methylphenidate.
DOSAGE AND ADMINISTRATION
Administration of Dose
Ritalin LA (methylphenidate hydrochloride) extended-release capsules are for oral administration once
daily in the morning. Ritalin LA may be swallowed as whole capsules or alternatively may be
administered by sprinkling the capsule contents on a small amount of applesauce (see specific
instructions below). Ritalin LA and/or their contents should not be crushed, chewed, or divided.
The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The
applesauce should not be warm because it could affect the modified release properties of this
formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The
drug and applesauce mixture should not be stored for future use. Patients should be advised to avoid
alcohol while taking Ritalin LA.
Dosing Recommendations
Dosage should be individualized according to the needs and responses of the patients.
Initial Treatment
The recommended starting dose of Ritalin LA is 20 mg once daily. Dosage may be adjusted in weekly
10 mg increments to a maximum of 60 mg/day taken once daily in the morning, depending on
tolerability and degree of efficacy observed. Daily dosage above 60 mg is not recommended. When in
the judgement of the clinician a lower initial dose is appropriate, patients may begin treatment with
Ritalin LA 10 mg.
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Patients Currently Receiving Methylphenidate
The recommended dose of Ritalin LA for patients currently taking methylphenidate b.i.d. or sustained
release (SR) is provided below.
Previous Methylphenidate Dose
Recommended Ritalin LA Dose
5 mg methylphenidate-b.i.d.
10 mg q.d.
10 mg methylphenidate b.i.d.
or 20 mg methylphenidate-SR
20 mg q.d.
15 mg methylphenidate b.i.d.
30 mg q.d.
20 mg methylphenidate b.i.d.
or 40 mg of methylphenidate-SR
40 mg q.d.
30 mg methylphenidate b.i.d.
or 60 mg methylphenidate-SR
60 mg q.d.
For other methylphenidate regimens, clinical judgment should be used when selecting the starting dose.
Ritalin LA dosage may be adjusted at weekly intervals in 10 mg increments.
Daily dosage above 60 mg is not recommended.
Maintenance/Extended Treatment
There is no body of evidence available from controlled trials to indicate how long the patient with
ADHD should be treated with Ritalin LA. It is generally agreed, however, that pharmacological
treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use
Ritalin LA for extended periods in patients with ADHD should periodically re-evaluate the long-term
usefulness of the drug for the individual patient with trials off medication to assess the patient’s
functioning without pharmacotherapy. Improvement may be sustained when the drug is either
temporarily or permanently discontinued.
Dose Reduction and Discontinuation
If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced,
or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate
dosage adjustment over a 1-month period, the drug should be discontinued.
HOW SUPPLIED
Ritalin LA capsules 10 mg: white/light brown (imprinted NVR R10)
Bottles of 100………………………………………………………NDC 0078-0424-05
Ritalin LA capsules 20 mg: white (imprinted NVR R20)
Bottles of 100………………………………………………………NDC 0078-0370-05
Ritalin LA capsules 30 mg: yellow (imprinted NVR R30)
Bottles of 100………………………………………………………NDC 0078-0371-05
Ritalin LA capsules 40 mg: light brown (imprinted NVR R40)
Bottles of 100………………………………………………………NDC 0078-0372-05
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Ritalin LA capsules 60 mg: light brown/yellow (imprinted NVR R60)
Bottles of 30………………………………………………………NDC 0078-0658-15
Store at 25°C (77°F), excursions permitted 15°C-30°C (59°F-86°F). [See USP controlled room
temperature]
Dispense in tight container (USP).
Ritalin LA is a trademark of Novartis AG.
SODAS® is a registered trademark of Alkermes Pharma Ireland Limited.
This product is covered by US patents including US 5,837,284 and 6,228,398.
REFERENCE
American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders. 4th edition.
Washington DC: American Psychiatric Association 1994.
T2015-XX
Month Year
Reference ID: 3734564
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MEDICATION GUIDE
RITALIN LA®
(methylphenidate hydrochloride) extended-release capsules CII
Read the Medication Guide that comes with RITALIN LA before you or your child starts taking it and
each time you get a refill. There may be new information. This Medication Guide does not take the
place of talking to your doctor about your or your child’s treatment with RITALIN LA.
What is the most important information I should know about RITALIN LA?
The following have been reported with use of methylphenidate hydrochloride and other
stimulant medicines.
1. Heart-related problems:
sudden death in patients who have heart problems or heart defects
stroke and heart attack in adults
increased blood pressure and heart rate
Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or a
family history of these problems.
Your doctor should check you or your child carefully for heart problems before starting RITALIN LA.
Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment
with RITALIN LA.
Call your doctor right away if you or your child has any signs of heart problems such as chest
pain, shortness of breath, or fainting while taking RITALIN LA.
2. Mental (Psychiatric) problems:
All Patients
new or worse behavior and thought problems
new or worse bipolar illness
new or worse aggressive behavior or hostility
Children and Teenagers
new psychotic symptoms (such as hearing voices, believing things that are not true, are
suspicious) or new manic symptoms
Tell your doctor about any mental problems you or your child have, or about a family history of
suicide, bipolar illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or
problems while taking RITALIN LA, especially seeing or hearing things that are not real,
believing things that are not real, or are suspicious.
3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s
phenomenon]: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to
blue, to red.
Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to
Reference ID: 3734564
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temperature in the fingers or toes.
Call your doctor right away if you have or your child has any signs of unexplained wounds
appearing on fingers or toes while taking Ritalin LA.
What Is RITALIN LA?
RITALIN LA is a central nervous system stimulant prescription medicine. It is used for the treatment
of Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN LA may help increase attention and
decrease impulsiveness and hyperactivity in patients with ADHD.
RITALIN LA should be used as a part of a total treatment program for ADHD that may include
counseling or other therapies.
RITALIN LA is a federally controlled substance (CII) because it can be abused or lead to
dependence. Keep RITALIN LA in a safe place to prevent misuse and abuse. Selling or giving
away RITALIN LA may harm others, and is against the law.
Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent
on alcohol, prescription medicines, or street drugs.
Who should not take RITALIN LA?
RITALIN LA should not be taken if you or your child:
are very anxious, tense, or agitated
have an eye problem called glaucoma
have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome. Tics are hard to
control repeated movements or sounds.
are taking or have taken within the past 14 days an anti-depression medicine called a monoamine
oxidase inhibitor or MAOI.
are allergic to anything in RITALIN LA. See the end of this Medication Guide for a complete list of
ingredients.
RITALIN LA should not be used in children less than 6 years old because it has not been studied in this
age group.
RITALIN LA may not be right for you or your child. Before starting RITALIN LA tell your or
your child’s doctor about all health conditions (or a family history of) including:
heart problems, heart defects, high blood pressure
mental problems including psychosis, mania, bipolar illness, or depression
tics or Tourette’s syndrome
seizures or have had an abnormal brain wave test (EEG)
circulation problems in fingers or toes
Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.
Reference ID: 3734564
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Can RITALIN LA be taken with other medicines?
Tell your doctor about all of the medicines that you or your child takes including prescription
and nonprescription medicines, vitamins, and herbal supplements. RITALIN LA and some
medicines may interact with each other and cause serious side effects. Sometimes the doses of other
medicines will need to be adjusted while taking RITALIN LA.
Your doctor will decide whether RITALIN LA can be taken with other medicines.
Especially tell your doctor if you or your child takes:
anti-depression medicines including MAOIs
seizure medicines
blood thinner medicines
blood pressure medicines
stomach acid medicines
cold or allergy medicines that contain decongestants
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your
doctor and pharmacist.
Do not start any new medicine while taking RITALIN LA without talking to your doctor first.
How should RITALIN LA be taken?
Take RITALIN LA exactly as prescribed. Your doctor may adjust the dose until it is right for
you or your child.
Take RITALIN LA once a day in the morning. RITALIN LA is an extended-release capsule. It
releases medicine into your body throughout the day.
Swallow RITALIN LA capsules whole with water or other liquids. If you cannot swallow the
capsule, open it and sprinkle the medicine over a spoonful of applesauce. Swallow the applesauce
and medicine mixture without chewing. Follow with a drink of water or other liquid. Never chew
or crush the capsule or the medicine inside the capsule.
RITALIN LA should not be taken with alcohol. This may result in a more rapid release of the
dose of RITALIN LA
From time to time, your doctor may stop RITALIN LA treatment for a while to check ADHD
symptoms.
Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN
LA. Children should have their height and weight checked often while taking RITALIN LA.
RITALIN LA treatment may be stopped if a problem is found during these check-ups.
If you or your child takes too much RITALIN LA or overdoses, call your doctor or poison
control center right away, or get emergency treatment.
What are possible side effects of RITALIN LA?
See “What is the most important information I should know about RITALIN LA” for information
on reported heart and mental problems.
Other serious side effects include:
Reference ID: 3734564
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slowing of growth (height and weight) in children
seizures, mainly in patients with a history of seizures
eyesight changes or blurred vision
painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your
child develop priapism, seek medical help right away. Because of the potential for lasting damage,
priapism should be evaluated by a doctor immediately.
Common side effects include:
headache
stomach ache
decreased appetite
trouble sleeping
Talk to your doctor if you or your child has side effects that are bothersome or do not go away.
This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.
How should I store RITALIN LA?
Store RITALIN LA in a safe place at room temperature, 59°F to 86°F (15°C to 30°C).
Keep RITALIN LA and all medicines out of the reach of children.
General information about RITALIN LA
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use RITALIN LA for a condition for which it was not prescribed. Do not give RITALIN LA to other
people, even if they have the same condition. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about RITALIN LA. If you would
like more information, talk with your doctor. You can ask your doctor or pharmacist for information
about RITALIN LA that was written for healthcare professionals. For more information about
RITALIN LA call 1-888-669-6682.
What are the ingredients in RITALIN LA?
Active Ingredient: methylphenidate HCL
Inactive Ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules
only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules
only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg
capsules).
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
By Alkermes Gainesville LLC
Gainesville, GA 30504
Reference ID: 3734564
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© Novartis
T2015-XX/T2013-124
Month Year/December 2013
Reference ID: 3734564
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|
custom-source
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|
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DRAXIMAGE® MDP-25
Kit for the Preparation of Technetium Tc 99m Medronate Injection
For Intravenous Use
DIAGNOSTIC – FOR SKELETAL IMAGING
DESCRIPTION
The kit consists of reaction vials which contain the sterile, non-pyrogenic, non-radioactive
ingredients necessary to produce Technetium Tc 99m Medronate Injection for diagnostic use by
intravenous injection. MDP-25 reaction vials are intended to be used as multidose vials.
Each 10 mL MDP-25 reaction vial contains 25.0 mg medronic acid and not less than 2.0 mg of
stannous chloride dihydrate (maximum total tin expressed as stannous chloride dihydrate 3.0 mg)
and 5.0 mg of p-aminobenzoic acid in lyophilized form under an atmosphere of nitrogen.
The pH is adjusted to 6.8 to 6.9 with HCI or NaOH prior to lyophilization. The addition of
sterile, non-pyrogenic, and oxidant-free sodium pertechnetate Tc-99m sterile solution produces a
rapid labeling which is essentially quantitative and which remains stable in vitro throughout the
12-hours life of the preparation. No bacteriostatic preservative is present.
The structural formula of medronic acid is:
O
O
HO
P
CH2
P
OH
OH
OH
PHYSICAL CHARACTERISTICS
Technetium Tc-99m decays by isomeric transition with a physical half-life of 6.02 hours.1 The
principal photon that is useful for detection and imaging studies is listed in Table 1.
Reference ID: 3019372
Reference ID: 3019508
1
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Table 1
PRINCIPAL RADIATION EMISSION DATA
Radiation
Mean %/
Disintegration
Energy
(keV)
Gamma-2
89.07
140.5
EXTERNAL RADIATION
The specific gamma ray constant for Tc-99m is 0.78 R/mCi-hr at 1 cm. The first half value layer
is 0.017 cm of lead. To facilitate control of the radiation exposure from millicurie amounts of
this radionuclide, the use of a 0.25 cm thickness of lead will attenuate the radiation emitted by a
factor of about 1,000. A range of values for the relative attenuation of the radiation emitted by
this radionuclide that results from interposition of various thicknesses of lead is shown in Table
2.
Table 2
RADIATION ATTENUATION BY LEAD SHIELDING
Shield Thickness
Coefficient of
(Pb) cm
Attenuation
0.017
0.5
0.08
10-1
0.16
10-2
0.25
10-3
0.33
10-4
To correct for physical decay of this radionuclide, the fractions that remain at selected intervals
after the time of calibration are shown in Table 3.
1Kocher, David C.: “Radioactive Decay Data Tables”, DOE/TIC-11026, 108 (1981)
2
Reference ID: 3019372
Reference ID: 3019508
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3
PHYSICAL DECAY CHART: Tc-99m, half-life 6.02 hours
Fraction
Fraction
Hours
Remaining
Hours
Remaining
0*
1.000
7
0.447
1
0.891
8
0.398
2
0.794
9
0.355
3
0.708
10
0.316
4
0.631
11
0.282
5
0.562
12
0.251
6
0.501
* Calibration time
CLINICAL PHARMACOLOGY
When injected intravenously, Technetium Tc 99m Medronate is rapidly cleared from the blood;
about 50% of the dose is accumulated and retained by the skeleton, while the remaining 50% is
excreted in the urine within 24 hours. About 10% of the injected dose remains in the blood at 1
hour post-injection, 5% at 2 hours, and less than 1% remains at 24 hours. The resultant blood
clearance curve is tri-exponential with the two fastest components accounting for all but a few
percent of the injected dose.
Following intravenous administration of Technetium Tc 99m Medronate, skeletal uptake occurs
as a function of blood flow to bone and bone efficiency in extracting the complex. Bone mineral
crystals are generally considered to be hydroxyapatite, and the complex appears to have an
affinity for the hydroxyapatite crystals in the bone.
The rapid blood clearance provides bone to soft-tissue ratios which favor early imaging. The
skeletal uptake is bilaterally symmetrical and is greater in the axial skeleton than in the long
bones. Areas of abnormal osteogenesis show altered uptake making it possible to visualize a
variety of osseous lesions.
INDICATIONS AND USAGE
MDP-25 (Kit for the Preparation of Technetium Tc 99m Medronate) may be used as a bone
imaging agent to delineate areas of altered osteogenesis.
3
Reference ID: 3019372
Reference ID: 3019508
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CONTRAINDICATIONS
None known at present.
WARNINGS
This class of compounds is known to complex cations such as calcium. Particular caution should
be used with patients who have, or who may be predisposed to, hypocalcemia (i.e., alkalosis).
The contents of the kit before preparation are not radioactive. However, after the sodium
pertechnetate Tc 99m is added, adequate shielding of the final preparation must be maintained.
Preliminary reports indicate impairment of brain images using sodium pertechnetate Tc 99m
injection which have been preceded by bone imaging using an agent containing stannous ions.
The impairment may result in false-positive or false-negative brain images. It is recommended,
where feasible, that brain imaging using sodium pertechnetate Tc 99m injection precede bone
imaging procedures. Alternatively, a brain imaging agent such as technetium Tc 99m pentetate
may be employed.
PRECAUTIONS
Contents of the reaction vial are intended only for use in the preparation of Technetium Tc 99m
Medronate and are NOT to be administered directly to the patient.
To minimize the radiation dose to the bladder, the patient should be encouraged to increase fluid
intake and to void as often as possible after the injection of Technetium Tc 99m Medronate, and
for 4 to 6 hours after the imaging procedure.
The preparation contains no bacteriostatic preservative.
Both the powdered and reconstituted forms of MDP-25 should be stored at 25°C (77°F);
excursions permitted between 15° and 30°C (59° to 86°F). The reconstituted product should be
stored in a suitable lead shield. The solution should not be used if it is cloudy.
Optimal imaging results are obtained 1 to 4 hours after administration. The image quality may be
adversely affected by obesity, old age and impaired renal function.
GENERAL
The components of the kit are sterile and non-pyrogenic. It is essential to follow directions
carefully and to adhere to strict aseptic procedures during preparation.
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4
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Technetium Tc 99m Medronate as well as other radioactive drugs must be handled with care.
Once sodium pertechnetate Tc-99m is added to the vial, appropriate safety measures should be
used to minimize external radiation to clinical occupational personnel. Care should also be taken
to minimize radiation exposure to patients in a manner consistent with proper patient
management.
The technetium Tc-99m labeling reactions involved depend on maintaining the stannous ion in
the reduced state. Hence, sodium pertechnetate Tc-99m containing oxidants should not be
employed.
Radiopharmaceuticals should be used only by physicians who are qualified by training and
experience in the safe use and handling of radionuclides and whose experience and training have
been approved by the appropriate government agency authorized to license the use of
radionuclides.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
No long term animal studies have been performed to evaluate carcinogenic or mutagenic
potential or whether Technetium Tc 99m Medronate affects fertility in males or females.
PREGNANCY CATEGORY C
Animal reproduction and teratogenicity studies have not been conducted with Technetium Tc
99m Medronate. It is also not known whether Technetium Tc 99m Medronate can cause fetal
harm when administered to a pregnant woman or can affect reproductive capacity. There have
been no studies in pregnant women. Technetium Tc 99m should be given to a pregnant woman
only if clearly needed.
Ideally, examinations using radiopharmaceuticals, especially those elective in nature, of a
woman of childbearing capability should be performed during the first few (approximately 10)
days following the onset of menses.
NURSING MOTHERS
Technetium Tc-99m is excreted in human milk during lactation. Therefore, formula feedings
should be substituted for breast feedings.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
Reference ID: 3019372
Reference ID: 3019508
5
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ADVERSE REACTIONS
Several cases of allergic dermatological reactions have been reported in association with the use
of Technetium Tc 99m Medronate.
Several reactions have also been reported in association with other radiopharmaceuticals of the
diphosphonate class, particularly Technetium Tc 99m Medronate. These are usually
hypersensitivity reactions characterized by itching, various skin rashes, hypotension, chills,
nausea, fever, and vomiting. One death secondary to cardiac arrhythmia following the
administration of Technetium Tc 99m Medronate has been reported. In addition, one case of
cardiac arrest in a patient also undergoing pulmonary function testing one and one-half hours
after the performance of a bone scan using Technetium Tc 99m Medronate has been reported.
DOSAGE AND ADMINISTRATION
The recommended adult dose, after reconstitution with oxidant-free sodium pertechnetate Tc
99m, is 370 to 740 megabecquerels (10 to 20 millicuries [200 µCi/kg]) by slow intravenous
injection over a period of 30 seconds. Optimum scanning time is 1 to 4 hours post-injection.
To minimize the contribution of the bladder content to the image, the patient should void
immediately before imaging is started.
The patient dose should be measured by a suitable radioactivity calibration system immediately
prior to administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration. The solution should not be used if cloudy.
RADIATION DOSIMETRY
The estimated absorbed radiation doses to an average patient (70 kg) from an intravenous
injection of a maximum dose of 740 megabecquerels (20 millicuries) of Technetium Tc 99m
Medronate are shown in Table 4. The effective half-life was assumed to be the physical half-life
for all calculated values.
6
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Table 4
RADIATION DOSES2
Tissue
Absorbed Radiation Dose
mGy/740 MBq
rads/20 mCi
Total Body
1.3
0.13
Total Bone
7.0
0.70
Red Marrow
5.6
0.56
Kidneys
8.0
0.80
Liver
Bladder Wall
0.6
0.06
2 hr. void
26.0
2.60
4.8 hr. void
Ovaries
62.0
6.20
2 hr. void
2.4
0.24
4.8 hr. void
Testes
3.4
0.34
2 hr. void
1.6
0.16
4.8 hr. void
2.2
0.22
2Method of calculation: “S” Absorbed Dose per Unit Cumulated Activity for Selected
Radionuclides and Organs, MIRD Pamphlet No. 11, 1975
HOW SUPPLIED
MDP-25, Kit for the Preparation of Technetium Tc 99m Medronate Injection
Product No. 500661 (30 vials)
Available in a box consisting of 30 reaction vials, each vial containing in lyophilized form,
sterile and non-pyrogenic:
Medronic Acid
25.0 mg
Stannous Chloride Dihydrate (minimum)
2.0 mg
(Maximum tin as stannous chloride dihydrate)
3.0 mg
p-Aminobenzoic Acid
5.0 mg
The pH is adjusted to 6.8 to 6.9 with HCI or NaOH prior to lyophilization. The vials are sealed
under an atmosphere of nitrogen.
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7
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Radioassay information labels with radiation warning symbol and a package insert are supplied
in each box.
STORAGE
Store the unreconstituted reaction vials at 25ºC (77ºF); excursions permitted between 15° and
30ºC (59° to 86ºF). After labeling with Technetium Tc-99m, the reconstituted product should be
stored at 25ºC (77ºF) in the original vial, and be placed in a suitable lead shield. Excursions
permitted between 15° and 30ºC (59° to 86ºF). Discard the reconstituted solution after 12 hours.
DIRECTIONS
NOTE:
Use aseptic procedures throughout and take precautions to minimize
radiation exposure by use of suitable shielding. Use waterproof gloves
during the following preparation procedure.
MDP-25 reaction vials are intended for the preparation of multiple doses of
technetium Tc-99m medronate and the entire contents of the vial should
not be used as a single dose.
Before reconstituting a vial, it should be inspected for cracks and/or a melted plug or any other
indication that the integrity of the vacuum seal has been compromised.
To prepare Technetium Tc 99m Medronate:
1.
Remove the central metal disc from a reaction vial and swab the closure with either an
alcohol swab or a suitable bacteriostatic agent.
2.
Place the reaction vial in a suitable lead vial shield (minimum wall thickness 1/8 inch)
which has a fitted lead cap. Obtain 2 to 10 mL of sterile, non-pyrogenic sodium
pertechnetate Tc-99m, using a shielded syringe.
The recommended maximum amount of Technetium Tc-99m to be added to a reaction
vial is 37.0 gigabecquerels (1000 mCi). Sufficient sodium pertechnetate is to be used for
the reconstitution of a reaction vial to ensure that the dose of medronate administered
does not exceed 10 mg. Sodium pertechnetate Tc-99m solutions containing an oxidizing
agent are not suitable for use.
3.
Using a shielded syringe, add the sodium pertechnetate Tc-99m solution to the reaction
vial aseptically.
4.
Place the lead cap on the reaction vial shield and agitate the shielded reaction vial until
Reference ID: 3019372
Reference ID: 3019508
8
This label may not be the latest approved by FDA.
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the contents are completely dissolved. The solution must be clear and free of particulate
matter before proceeding.
5.
Assay the product in a suitable calibrator, record the radioassay information on the label
with radiation warning symbol, and apply it to the reaction vial.
6.
Withdrawals for administration must be made aseptically using a shielded sterile syringe
and needle. Since the reaction vials contain nitrogen to prevent oxidation of the complex,
they should not be vented. If repeated withdrawals are made, minimize the replacement
of contents with room air.
The following steps should be followed to ensure that each reconstituted of technetium
Tc 99m Medronate contains between 1 and 10 mg of medronic acid.
Where:
Vr
= Final volume of in the vial in mL after reconstitution.
C
= Concentration of Medronic Acid in mg/mL.
Max. V = Maximum volume to be used for one dose in mL.
Min. V =Minimum volume to be used for one dose in mL.
a) Prior to reconstitution, determine the radioactive concentration of the sodium
pertechnetate Tc-99m.
b) Note the volume and activity added to the vial. It should be between 1.85 – 37.0 GBq
(50 – 1000 mCi) in 1 to 10 mL.
c) Calculate the concentration (C) of Medronic acid in the vial after reconstitution.
C (mg/mL)
=
25 mg
÷
Vr (mL)
d) To ensure that the dose contains a maximum of 10 mg, the following formula should
be used to calculate the maximum volume (Max. V) to be dispensed as one dose.
Max. V (mL)
=
10 mg
÷
C (mg/mL)
e) To ensure that a minimum dose of 1 mg is dispensed, the following formula should be
used to calculate the minimum volume (Min. V) to be dispensed as one dose
Min. V
=
1 mg
÷
C (mg/mL)
7.
The finished preparation should be stored at 25ºC (77ºF); excursions permitted between
15° and 30ºC (59° to 86ºF) when not in use and discarded after 12 hours. It should also be
Reference ID: 3019372
Reference ID: 3019508
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
stored during its life in a suitable lead shield.
This reagent kit is approved by the U.S. Nuclear Regulatory Commission for distribution to
persons licensed to use by-product material identified in §35.200 to 10 CFR Part 35, to persons
who have a similar authorization issued by an Agreement State, and, outside the United States, to
persons authorized by the appropriate authority.
NDC 65174-660-30 (30 vials)
Manufactured by:
Jubilant DraxImage Inc.
Kirkland, Quebec H9H 4J4 Canada
Issued Date
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:30.842927
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018035s032lbl.pdf', 'application_number': 18035, 'submission_type': 'SUPPL ', 'submission_number': 32}
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NDA 18031/S-036
Page 3
INDERIDE®
(propranolol hydrochloride [Inderal®]
and hydrochlorothiazide)
Rx only
DESCRIPTION
Inderide Tablets for oral administration combine two antihypertensive agents: Inderal
(propranolol hydrochloride), a beta-adrenergic blocking agent, and hydrochlorothiazide, a
thiazide diuretic-antihypertensive. Inderide 40/25 Tablets contain 40 mg propranolol
hydrochloride and 25 mg hydrochlorothiazide; Inderide 80/25 Tablets contain 80 mg propranolol
hydrochloride and 25 mg hydrochlorothiazide.
Inderal (propranolol hydrochloride) is a synthetic beta-adrenergic receptor-blocking agent
chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-,
Structural Formula
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water
and ethanol. Its molecular weight is 295.80.
Hydrochlorothiazide is a white, or practically white, practically odorless, crystalline powder. It
is slightly soluble in water; freely soluble in sodium hydroxide solution; sparingly soluble in
methanol; insoluble in ether, chloroform, benzene, and dilute mineral acids. Its chemical name
is: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its structural
formula is: Structural Formula
The inactive ingredients contained in Inderide Tablets are lactose, magnesium stearate,
microcrystalline cellulose, stearic acid, and yellow ferric oxide.
CLINICAL PHARMACOLOGY
Propranolol hydrochloride (Inderal)
Propranolol hydrochloride is a nonselective beta-adrenergic receptor blocking agent possessing
no other autonomic nervous system activity. It specifically competes with beta-adrenergic
receptor stimulating agents for available receptor sites. When access to beta-receptor sites is
blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic
stimulation are decreased proportionately.
Propranolol is almost completely absorbed from the gastrointestinal tract, but a portion is
immediately metabolized by the liver on its first pass through the portal circulation.
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NDA 18031/S-036
Page 4
Peak effect occurs in one to one-and-one-half hours. The biologic half-life is approximately four
hours. Propranolol is not significantly dialyzable. There is no simple correlation between dose
or plasma level and therapeutic effect, and the dose-sensitivity range, as observed in clinical
practice, is wide. The principal reason for this is that sympathetic tone varies widely between
individuals. Since there is no reliable test to estimate sympathetic tone or to determine whether
total beta blockade has been achieved, proper dosage requires titration.
The mechanism of the antihypertensive effect of propranolol has not been established. Among
the factors that may be involved in contributing to the antihypertensive action are (1) decreased
cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic
sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral
resistance may increase initially, it readjusts to, or below, the pretreatment level with chronic
use. Effects on plasma volume appear to be minor and somewhat variable. Propranolol has been
shown to cause a small increase in serum potassium concentration when used in the treatment of
hypertensive patients. Propranolol hydrochloride decreases heart rate, cardiac output, and blood
pressure.
Beta-receptor blockade can be useful in conditions in which, because of pathologic or functional
changes, sympathetic activity is detrimental to the patient. But there are also situations in which
sympathetic stimulation is vital. For example, in patients with severely damaged hearts,
adequate ventricular function is maintained by virtue of sympathetic drive, which should be
preserved. In the presence of AV block greater than first degree, beta blockade may prevent the
necessary facilitating effect of sympathetic activity on conduction. Beta blockade results in
bronchial constriction by interfering with adrenergic bronchodilator activity, which should be
preserved in patients subject to bronchospasm.
The proper objective of beta-blockade therapy is to decrease adverse sympathetic stimulation,
but not to the degree that may impair necessary sympathetic support.
Hydrochlorothiazide
Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic closely related to chlorothiazide.
The mechanism of the antihypertensive effect of the thiazides is unknown. Thiazides do not
affect normal blood pressure.
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal
therapeutic dosage, all thiazides are approximately equal in their diuretic potency.
Thiazides increase excretion of sodium and chloride in approximately equivalent amounts.
Natriuresis causes a secondary loss of potassium and bicarbonate. Onset of diuretic action of
hydrochlorothiazide occurs in two hours, and the peak effect in about four hours. Its action
persists for approximately six to 12 hours. Thiazides are eliminated rapidly by the kidney.
INDICATIONS AND USAGE
Inderide is indicated in the management of hypertension.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18031/S-036
Page 5
This fixed combination is not indicated for initial therapy of hypertension. Hypertension
requires therapy titrated to the individual patient. If the fixed combination represents the
dosage so determined, its use may be more convenient in patient management.
CONTRAINDICATIONS
Propranolol hydrochloride (Inderal)
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than
first-degree block; 3) bronchial asthma; 4) congestive heart failure (see “WARNINGS”) unless
the failure is secondary to a tachyarrhythmia treatable with propranolol.
Hydrochlorothiazide
Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other
sulfonamide-derived drugs.
WARNINGS
Propranolol hydrochloride (Inderal)
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated
with the administration of propranolol and hydrochlorothiazide (see “ADVERSE
REACTIONS”).
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function
in congestive heart failure, and inhibition with beta blockade always carries the potential hazard
of further depressing myocardial contractility and precipitating cardiac failure. Propranolol acts
selectively without abolishing the inotropic action of digitalis on the heart muscle (i.e., that of
supporting the strength of myocardial contractions). In patients already receiving digitalis, the
positive inotropic action of digitalis may be reduced by propranolol's negative inotropic effect.
Patients Without a History of Heart Failure: Continued depression of the myocardium over a
period of time can, in some cases, lead to cardiac failure. In rare instances, this has been
observed during propranolol therapy. Therefore, at the first sign or symptom of impending
cardiac failure, patients should be fully digitalized and/or given additional diuretic, and the
response observed closely: a) if cardiac failure continues, despite adequate digitalization and
diuretic therapy, propranolol therapy should be withdrawn (gradually, if possible); b) if
tachyarrhythmia is being controlled, patients should be maintained on combined therapy and the
patient closely followed until threat of cardiac failure is over.
Angina Pectoris: There have been reports of exacerbation of angina and, in some cases,
myocardial infarction following abrupt discontinuation of propranolol therapy. Therefore,
when discontinuance of propranolol is planned, the dosage should be gradually reduced and the
patient should be carefully monitored. In addition, when propranolol is prescribed for angina
pectoris, the patient should be cautioned against interruption or cessation of therapy without the
physician's advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it
usually is advisable to reinstitute propranolol therapy and take other measures appropriate for
the management of unstable angina pectoris. Since coronary artery disease may be
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18031/S-036
Page 6
unrecognized, it may be prudent to follow the above advice in patients considered at risk of
having occult atherosclerotic heart disease, who are given propranolol for other indications.
Nonallergic Bronchospasm: (e.g., chronic bronchitis, emphysema): PATIENTS WITH
BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA
BLOCKERS. Propranolol should be administered with caution since it may block
bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta
receptors.
Major Surgery: The necessity or desirability of withdrawal of beta-blocking therapy prior to
major surgery is controversial. It should be noted, however, that the impaired ability of the heart
to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical
procedures.
Propranolol, like other beta blockers, is a competitive inhibitor of beta-receptor agonists, and its
effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol.
However, such patients may be subject to protracted severe hypotension. Difficulty in starting
and maintaining the heartbeat has also been reported with beta blockers.
Diabetes and Hypoglycemia: Beta-adrenergic blockade may prevent the appearance of certain
premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia in
labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage
of insulin. Hypoglycemic attack may be accompanied by a precipitous elevation of blood
pressure in patients on propranolol.
Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with
hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has
been found after this type of drug therapy and prolonged physical exertion and has occurred in
renal insufficiency, both during dialysis and sporadically, in patients on propranolol.
Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients
on propranolol.
Thyrotoxicosis: Beta blockade may mask certain clinical signs of hyperthyroidism. Therefore,
abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of
hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests,
increasing T4 and reverse T3, and decreasing T3.
Wolff-Parkinson-White Syndrome: Several cases have been reported in which, after
propranolol, the tachycardia was replaced by a severe bradycardia requiring a demand
pacemaker. In one case this resulted after an initial dose of 5 mg propranolol.
Skin Reactions: Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal
necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with
use of propranolol (see “ADVERSE REACTIONS”).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18031/S-036
Page 7
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease,
thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects
of the drug may develop.
Thiazides should also be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation
occurs with ganglionic or peripheral adrenergic-blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma. The
possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
PRECAUTIONS
General
Propranolol hydrochloride (Inderal)
Propranolol should be used with caution in patients with impaired hepatic or renal function.
Inderide is not indicated for the treatment of hypertensive emergencies.
Risk of anaphylactic reaction. While taking beta blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat allergic reaction.
Hydrochlorothiazide
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine
electrolyte determinations are particularly important when the patient is vomiting excessively or
receiving parenteral fluids. Medication such as digitalis may also influence serum electrolytes.
Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy,
drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria,
tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia.
Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis
(e.g., increased ventricular irritability).
Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high
potassium content.
Any chloride deficit is generally mild, and usually does not require specific treatment except
under extraordinary circumstances (as in liver or renal disease). Dilutional hyponatremia may
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18031/S-036
Page 8
occur in edematous patients in hot weather; appropriate therapy is water restriction rather than
administration of salt, except in rare instances when the hyponatremia is life-threatening. In
actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
Diabetes mellitus which has been latent may become manifest during thiazide administration.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic
therapy.
Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid gland with
hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged
thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis,
bone resorption, and peptic ulceration, have not been seen.
Information for Patients
Beta-adrenoreceptor blockade can cause reduction of intraocular pressure. Patients should be
told that Inderide may interfere with the glaucoma screening test. Withdrawal may lead to a
return of increased intraocular pressure.
Laboratory Tests
Propranolol hydrochloride (Inderal)
Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase,
alkaline phosphatase, lactate dehydrogenase.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be
performed at appropriate intervals.
Drug/Drug Interactions
Propranolol hydrochloride (Inderal)
Patients receiving catecholamine-depleting drugs such as reserpine should be closely observed if
Inderide is administered. The added catecholamine-blocking action may produce an excessive
reduction of resting sympathetic nervous activity, which may result in hypotension, marked
bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
Caution should be exercised when patients receiving a beta blocker are administered a calcium-
channel blocking drug, especially intravenous verapamil, for both agents may depress
myocardial contractility or atrioventricular conduction. On rare occasions, the concomitant
intravenous use of a beta blocker and verapamil has resulted in serious adverse reactions,
especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial
infarction.
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NDA 18031/S-036
Page 9
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart
rate. Concomitant use can increase the risk of bradycardia.
Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal
anti-inflammatory drugs has been reported.
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and
haloperidol.
Aluminum hydroxide gel greatly reduces intestinal absorption of propranolol.
Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.
Phenytoin, phenobarbitone, and rifampin accelerate propranolol clearance.
Chlorpromazine, when used concomitantly with propranolol, results in increased plasma levels
of both drugs.
Antipyrine and lidocaine have reduced clearance when used concomitantly with propranolol.
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with
propranolol.
Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination and increasing
blood levels.
Theophylline clearance is reduced when used concomitantly with propranolol.
Hydrochlorothiazide
Thiazide drugs may increase the responsiveness to tubocurarine.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not
sufficient to preclude effectiveness of the pressor agent for therapeutic use.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Hypokalemia may develop during concomitant use of corticosteroids or ACTH.
Drug/Laboratory Test Interactions
Hydrochlorothiazide
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function (see
“PRECAUTIONS—General”).
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NDA 18031/S-036
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Combinations of propranolol and hydrochlorothiazide have not been evaluated for carcinogenic
or mutagenic potential or for potential to adversely affect fertility.
Propranolol hydrochloride (Inderal)
In dietary administration studies in which mice and rats were treated with propranolol for up to
18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis.
In a study in which both male and female rats were exposed to propranolol in their diets at
concentrations of up to 0.05%, from 60 days prior to mating and throughout pregnancy and
lactation for two generations, there were no effects on fertility. Based on differing results from
Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic
effect of propranolol in bacteria (S.typhimurium strain TA 1538).
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National
Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male
and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found
equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames bacterial mutagen assay
(S.typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538) or in the Chinese
Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays
using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the
Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the
in vitro CHO Sister Chromatid Exchange (clastogenicity), Mouse Lymphoma Cell
(mutagenicity) and Aspergillus nidulans non-disjunction assays.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and
4 mg/kg, respectively, prior to mating and throughout gestation.
Pregnancy: Pregnancy Category C
Combinations of propranolol and hydrochlorothiazide have not been evaluated for effects on
pregnancy in animals. Nor are there adequate and well-controlled studies of propranolol,
hydrochlorothiazide, or Inderide in pregnant women. Inderide should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Propranolol hydrochloride (Inderal)
In a series of reproduction and developmental toxicology studies, propranolol was given to rats
by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day
(>30 times the dose of propranolol contained in the maximum recommended human daily dose
of Inderide), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity
(reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths).
Propranolol also was administered (in the feed) to rabbits (throughout pregnancy and lactation)
at doses as high as 150 mg/kg/day (>45 times the dose of propranolol contained in the maximum
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NDA 18031/S-036
Page 11
recommended daily human dose of Inderide). No evidence of embryo or neonatal toxicity was
noted.
Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported
in human neonates whose mothers received propranolol during pregnancy. Neonates whose
mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia and/or
respiratory depression. Adequate facilities for monitoring these infants at birth should be
available.
Hydrochlorothiazide
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats at doses
of up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.
Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant
women requires that the anticipated benefit be weighed against possible hazards to the fetus.
These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse
reactions that have occurred in the adult.
Nursing Mothers
Propranolol hydrochloride (Inderal)
Propranolol is excreted in human milk. Caution should be exercised when Inderide is
administered to a nursing woman.
Hydrochlorothiazide
Thiazides appear in breast milk. If the use of drug is deemed essential, the patient should stop
nursing.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Inderide did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
The following adverse reactions have been observed, but there is not enough systematic
collection of data to support an estimate of their frequency. Within each category, adverse
reactions are listed in decreasing order of severity. Although many side effects are mild and
transient, some require discontinuation of therapy.
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NDA 18031/S-036
Page 12
Propranolol hydrochloride (Inderal)
Cardiovascular: Congestive heart failure; hypotension; intensification of AV block; bradycardia;
thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type; paresthesia of
hands.
Central Nervous System: Reversible mental depression progressing to catatonia; mental
depression manifested by insomnia, lassitude, weakness, fatigue; an acute reversible syndrome
characterized by disorientation for time and place, short-term memory loss, emotional lability,
slightly clouded sensorium, decreased performance on neuropsychometrics; hallucinations;
visual disturbances; vivid dreams; light-headedness. Total daily doses above 160 mg (when
administered as divided doses of greater than 80 mg each) may be associated with an increased
incidence of fatigue, lethargy, and vivid dreams.
Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis; nausea, vomiting, epigastric
distress, abdominal cramping, diarrhea, constipation.
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions;
laryngospasm and respiratory distress; pharyngitis and agranulocytosis; fever combined with
aching and sore throat; erythematous rash.
Respiratory: Bronchospasm.
Hematologic: Agranulocytosis; nonthrombocytopenic purpura; thrombocytopenic purpura.
Autoimmune: In extremely rare instances, systemic lupus erythematosus has been reported.
Miscellaneous: Male impotence. Alopecia, LE-like reactions, psoriasiform rashes, dry eyes, and
Peyronie's disease have been reported rarely. Oculomucocutaneous reactions involving the skin,
serous membranes, and conjunctivae reported for a beta blocker (practolol) have not been
associated with propranolol.
Skin: Stevens-Johnson Syndrome; toxic epidermal necrolysis; exfoliative dermatitis; erythema
multiforme; urticaria.
Hydrochlorothiazide
Cardiovascular: Orthostatic hypotension (may be aggravated by alcohol, barbiturates or
narcotics).
Central Nervous System: Dizziness, vertigo, headache, xanthopsia, paresthesias.
Gastrointestinal: Pancreatitis; jaundice (intrahepatic cholestatic jaundice); sialadenitis; anorexia,
nausea, vomiting, gastric irritation, cramping, diarrhea, constipation.
Hypersensitivity: Anaphylactic reactions; necrotizing angiitis (vasculitis, cutaneous vasculitis);
respiratory distress including pneumonitis; fever; urticaria, rash, purpura, photosensitivity.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
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NDA 18031/S-036
Page 13
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis
including toxic epidermal necrolysis.
Miscellaneous: Hyperglycemia, glycosuria; hyperuricemia; muscle spasm; weakness;
restlessness; transient blurred vision.
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or
therapy withdrawn.
OVERDOSAGE
The propranolol hydrochloride component may cause bradycardia, cardiac failure, hypotension,
or bronchospasm. Propranolol is not significantly dialyzable.
The hydrochlorothiazide component can be expected to cause diuresis. Lethargy of varying
degree may appear and may progress to coma within a few hours, with minimal depression of
respiration and cardiovascular function, and in the absence of significant serum electrolyte
changes or dehydration. The mechanism of central nervous system depression with thiazide
overdosage is unknown. Gastrointestinal irritation and hypermotility can occur, temporary
elevation of BUN has been reported, and serum electrolyte changes could occur, especially in
patients with impairment of renal function.
The oral LD50 dosages in rats and mice for propranolol, hydrochlorothiazide, and combined
propranolol/hydrochlorothiazide (40/25, 80/25) are 364 to 533 mg/kg, greater than
2,750 to 5,000 mg/kg, and 538 to 845 mg/kg, respectively.
Treatment
The following measures should be employed:
General—If ingestion is, or may have been, recent, evacuate gastric contents, taking care to
prevent pulmonary aspiration.
Bradycardia—Administer atropine (0.25 to 1.0 mg). If there is no response to vagal blockade,
administer isoproterenol cautiously.
Cardiac Failure—Digitalization and diuretics.
Hypotension—Vasopressors, e.g., levarterenol or epinephrine.
Bronchospasm—Administer isoproterenol and aminophylline.
Stupor or Coma—Administer supportive therapy as clinically warranted.
Gastrointestinal Effects—Though usually of short duration, these may require symptomatic
treatment.
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NDA 18031/S-036
Page 14
Abnormalities in BUN and/or Serum Electrolytes—Monitor serum electrolyte levels and renal
function; institute supportive measures as required individually to maintain hydration, electrolyte
balance, respiration, and cardiovascular-renal function.
DOSAGE AND ADMINISTRATION
The dosage must be determined by individual titration.
Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. The initial
dose of propranolol is 80 mg daily, and it may be increased gradually until optimal blood
pressure control is achieved. The usual effective dose when used alone is 160 to 480 mg per day.
One Inderide Tablet twice daily can be used to administer up to 160 mg of propranolol and
50 mg of hydrochlorothiazide. For doses of propranolol greater than 160 mg the combination
products are not appropriate, because their use would lead to an excessive dose of the thiazide
component.
When necessary, another antihypertensive agent may be added gradually beginning with
50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure.
HOW SUPPLIED
Inderide 40/25
Each hexagonal-shaped, off-white, scored tablet, embossed with an “I” and imprinted with
“INDERIDE 40/25,” contains 40 mg propranolol hydrochloride (Inderal®) and 25 mg
hydrochlorothiazide, in bottles of 100 (NDC 24090-0484-88).
Inderide 80/25
Each hexagonal-shaped, off-white, scored tablet, embossed with an “I” and imprinted with
“INDERIDE 80/25,” contains 80 mg propranolol hydrochloride (Inderal®) and 25 mg
hydrochlorothiazide, in bottles of 100 (NDC 24090-0488-88).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°-30°C (59°-86°C). [See USP
Controlled Room Temperature]
Protect from moisture, freezing, and excessive heat.
Dispense in a well-closed container as defined in the USP.
The appearance of these tablets is a registered trademark of Wyeth Pharmaceuticals.
This product’s label may have been updated. For current package insert and
further product information, call our medical communications department
toll-free at 1-800-934-5556 888-383 1733
. Computer GrapicTelephone graphic
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NDA 18031/S-036
Page 15
Manufactured for Akrimax Pharmaceuticals, LLC
Cranford, NJ 07016
By Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
(Update 248F400)
Rev Date 11/09
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:30.843261
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018031s036lbl.pdf', 'application_number': 18031, 'submission_type': 'SUPPL ', 'submission_number': 36}
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11,128
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INDERIDE®
(propranolol hydrochloride [Inderal®]
and hydrochlorothiazide)
Rx only
DESCRIPTION
Inderide Tablets for oral administration combine two antihypertensive agents: Inderal
(propranolol hydrochloride), a beta-adrenergic blocking agent, and hydrochlorothiazide, a
thiazide diuretic-antihypertensive. Inderide 40/25 Tablets contain 40 mg propranolol
hydrochloride and 25 mg hydrochlorothiazide; Inderide 80/25 Tablets contain 80 mg propranolol
hydrochloride and 25 mg hydrochlorothiazide.
Inderal (propranolol hydrochloride) is a synthetic beta-adrenergic receptor-blocking agent
chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-,
hydrochloride,(±)-. Its structural formula is: structural formula
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water
and ethanol. Its molecular weight is 295.80.
Hydrochlorothiazide is a white, or practically white, practically odorless, crystalline powder. It is
slightly soluble in water; freely soluble in sodium hydroxide solution; sparingly soluble in
methanol; insoluble in ether, chloroform, benzene, and dilute mineral acids. Its chemical name
is: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its structural
formula is: structural formula
The inactive ingredients contained in Inderide Tablets are lactose, magnesium stearate,
microcrystalline cellulose, stearic acid, and yellow ferric oxide.
CLINICAL PHARMACOLOGY
Propranolol hydrochloride (Inderal®)
Propranolol hydrochloride is a nonselective beta-adrenergic receptor blocking agent possessing
no other autonomic nervous system activity. It specifically competes with beta-adrenergic
receptor stimulating agents for available receptor sites. When access to beta-receptor sites is
blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic
stimulation are decreased proportionately.
Propranolol is almost completely absorbed from the gastrointestinal tract, but a portion is
immediately metabolized by the liver on its first pass through the portal circulation.
1
Reference ID: 2919393
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Peak effect occurs in one to one-and-one-half hours. The biologic half-life is approximately four
hours. Propranolol is not significantly dialyzable. There is no simple correlation between dose or
plasma level and therapeutic effect, and the dose-sensitivity range, as observed in clinical
practice, is wide. The principal reason for this is that sympathetic tone varies widely between
individuals. Since there is no reliable test to estimate sympathetic tone or to determine whether
total beta blockade has been achieved, proper dosage requires titration.
The mechanism of the antihypertensive effect of propranolol has not been established. Among
the factors that may be involved in contributing to the antihypertensive action are (1) decreased
cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic
sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral
resistance may increase initially, it readjusts to, or below, the pretreatment level with chronic
use. Effects on plasma volume appear to be minor and somewhat variable. Propranolol has been
shown to cause a small increase in serum potassium concentration when used in the treatment of
hypertensive patients. Propranolol hydrochloride decreases heart rate, cardiac output, and blood
pressure.
Beta-receptor blockade can be useful in conditions in which, because of pathologic or functional
changes, sympathetic activity is detrimental to the patient. But there are also situations in which
sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate
ventricular function is maintained by virtue of sympathetic drive, which should be preserved. In
the presence of AV block greater than first degree, beta blockade may prevent the necessary
facilitating effect of sympathetic activity on conduction. Beta blockade results in bronchial
constriction by interfering with adrenergic bronchodilator activity, which should be preserved in
patients subject to bronchospasm.
The proper objective of beta-blockade therapy is to decrease adverse sympathetic stimulation,
but not to the degree that may impair necessary sympathetic support.
Hydrochlorothiazide
Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic closely related to chlorothiazide.
The mechanism of the antihypertensive effect of the thiazides is unknown. Thiazides do not
affect normal blood pressure.
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic
dosage, all thiazides are approximately equal in their diuretic potency.
Thiazides increase excretion of sodium and chloride in approximately equivalent amounts.
Natriuresis causes a secondary loss of potassium and bicarbonate. Onset of diuretic action of
hydrochlorothiazide occurs in two hours, and the peak effect in about four hours. Its action
persists for approximately six to 12 hours. Thiazides are eliminated rapidly by the kidney.
INDICATIONS AND USAGE
Inderide is indicated in the management of hypertension.
This fixed combination is not indicated for initial therapy of hypertension. Hypertension
requires therapy titrated to the individual patient. If the fixed combination represents the
dosage so determined, its use may be more convenient in patient management.
2
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
Propranolol hydrochloride (Inderal®)
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than
first-degree block; 3) bronchial asthma; 4) congestive heart failure (see “WARNINGS”) unless
the failure is secondary to a tachyarrhythmia treatable with propranolol.
Hydrochlorothiazide
Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other
sulfonamide-derived drugs.
WARNINGS
Propranolol hydrochloride (Inderal®)
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated
with the administration of propranolol and hydrochlorothiazide (see “ADVERSE
REACTIONS”).
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function
in congestive heart failure, and inhibition with beta blockade always carries the potential hazard
of further depressing myocardial contractility and precipitating cardiac failure. Propranolol acts
selectively without abolishing the inotropic action of digitalis on the heart muscle (i.e., that of
supporting the strength of myocardial contractions). In patients already receiving digitalis, the
positive inotropic action of digitalis may be reduced by propranolol's negative inotropic effect.
Patients Without a History of Heart Failure: Continued depression of the myocardium over a
period of time can, in some cases, lead to cardiac failure. In rare instances, this has been
observed during propranolol therapy. Therefore, at the first sign or symptom of impending
cardiac failure, patients should be fully digitalized and/or given additional diuretic, and the
response observed closely: a) if cardiac failure continues, despite adequate digitalization and
diuretic therapy, propranolol therapy should be withdrawn (gradually, if possible); b) if
tachyarrhythmia is being controlled, patients should be maintained on combined therapy and the
patient closely followed until threat of cardiac failure is over.
Angina Pectoris: There have been reports of exacerbation of angina and, in some cases,
myocardial infarction following abrupt discontinuation of propranolol therapy. Therefore, when
discontinuance of propranolol is planned, the dosage should be gradually reduced and the
patient should be carefully monitored. In addition, when propranolol is prescribed for angina
pectoris, the patient should be cautioned against interruption or cessation of therapy without the
physician's advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it
usually is advisable to reinstitute propranolol therapy and take other measures appropriate for
the management of unstable angina pectoris. Since coronary artery disease may be
unrecognized, it may be prudent to follow the above advice in patients considered at risk of
having occult atherosclerotic heart disease, who are given propranolol for other indications.
3
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema): PATIENTS WITH
BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA
BLOCKERS. Propranolol should be administered with caution since it may block
bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta
receptors.
Major Surgery: Chronically administered beta-blocking therapy should not be routinely withdrawn
prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli
may augment the risks of general anesthesia and surgical procedures.
Diabetes and Hypoglycemia: Beta-adrenergic blockade may prevent the appearance of certain
premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia in
labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage
of insulin. Hypoglycemic attack may be accompanied by a precipitous elevation of blood
pressure in patients on propranolol.
Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with
hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has
been found after this type of drug therapy and prolonged physical exertion and has occurred in
renal insufficiency, both during dialysis and sporadically, in patients on propranolol.
Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients
on propranolol.
Thyrotoxicosis: Beta blockade may mask certain clinical signs of hyperthyroidism. Therefore,
abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of
hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests,
increasing T4 and reverse T3, and decreasing T3.
Wolff-Parkinson-White Syndrome: Several cases have been reported in which, after
propranolol, the tachycardia was replaced by a severe bradycardia requiring a demand
pacemaker. In one case this resulted after an initial dose of 5 mg propranolol.
Skin Reactions: Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal
necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with
use of propranolol (see “ADVERSE REACTIONS”).
Hydrochlorothiazide
Thiazides should be used with caution in severe renal disease. In patients with renal disease,
thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects
of the drug may develop.
Thiazides should also be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma.
4
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs
with ganglionic or peripheral adrenergic-blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma. The
possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Acute Myopia and Secondary Angle-closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute
transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased
visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary
treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or
surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.
Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide
or penicillin allergy.
PRECAUTIONS
General
Propranolol hydrochloride (Inderal®)
Propranolol should be used with caution in patients with impaired hepatic or renal function.
Inderide is not indicated for the treatment of hypertensive emergencies.
Risk of anaphylactic reaction. While taking beta blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat allergic reaction.
Hydrochlorothiazide
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte
imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine
electrolyte determinations are particularly important when the patient is vomiting excessively or
receiving parenteral fluids. Medication such as digitalis may also influence serum electrolytes.
Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy,
drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria,
tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia.
Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis
(e.g., increased ventricular irritability).
Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high
potassium content.
Any chloride deficit is generally mild, and usually does not require specific treatment except
under extraordinary circumstances (as in liver or renal disease). Dilutional hyponatremia may
occur in edematous patients in hot weather; appropriate therapy is water restriction rather than
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Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
administration of salt, except in rare instances when the hyponatremia is life-threatening. In
actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
Diabetes mellitus which has been latent may become manifest during thiazide administration.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic
therapy.
Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid gland with
hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged
thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis,
bone resorption, and peptic ulceration, have not been seen.
Information for Patients
Beta-adrenoreceptor blockade can cause reduction of intraocular pressure. Patients should be told
that Inderide may interfere with the glaucoma screening test. Withdrawal may lead to a return of
increased intraocular pressure.
Laboratory Tests
Propranolol hydrochloride (Inderal®)
Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase,
alkaline phosphatase, lactate dehydrogenase.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be
performed at appropriate intervals.
Drug/Drug Interactions
Propranolol hydrochloride (Inderal®)
Patients receiving catecholamine-depleting drugs such as reserpine should be closely observed if
Inderide is administered. The added catecholamine-blocking action may produce an excessive
reduction of resting sympathetic nervous activity, which may result in hypotension, marked
bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
Caution should be exercised when patients receiving a beta blocker are administered a calcium-
channel blocking drug, especially intravenous verapamil, for both agents may depress
myocardial contractility or atrioventricular conduction. On rare occasions, the concomitant
intravenous use of a beta blocker and verapamil has resulted in serious adverse reactions,
especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial
infarction.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart
rate. Concomitant use can increase the risk of bradycardia.
6
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal
anti-inflammatory drugs has been reported.
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and
haloperidol.
Aluminum hydroxide gel greatly reduces intestinal absorption of propranolol.
Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.
Phenytoin, phenobarbitone, and rifampin accelerate propranolol clearance.
Chlorpromazine, when used concomitantly with propranolol, results in increased plasma levels
of both drugs.
Antipyrine and lidocaine have reduced clearance when used concomitantly with propranolol.
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with
propranolol.
Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination and increasing
blood levels.
Theophylline clearance is reduced when used concomitantly with propranolol.
Hydrochlorothiazide
Thiazide drugs may increase the responsiveness to tubocurarine.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not
sufficient to preclude effectiveness of the pressor agent for therapeutic use.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Hypokalemia may develop during concomitant use of corticosteroids or ACTH.
Drug/Laboratory Test Interactions
Hydrochlorothiazide
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function (see
“PRECAUTIONS—General”).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Combinations of propranolol and hydrochlorothiazide have not been evaluated for carcinogenic
or mutagenic potential or for potential to adversely affect fertility.
Propranolol hydrochloride (Inderal®)
In dietary administration studies in which mice and rats were treated with propranolol for up to
18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis.
7
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In a study in which both male and female rats were exposed to propranolol in their diets at
concentrations of up to 0.05%, from 60 days prior to mating and throughout pregnancy and
lactation for two generations, there were no effects on fertility. Based on differing results from
Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic
effect of propranolol in bacteria (S.typhimurium strain TA 1538).
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National
Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male
and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found
equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames bacterial mutagen assay
(S.typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538) or in the Chinese
Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays
using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the
Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the
in vitro CHO Sister Chromatid Exchange (clastogenicity), Mouse Lymphoma Cell
(mutagenicity) and Aspergillus nidulans non-disjunction assays.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and
4 mg/kg, respectively, prior to mating and throughout gestation.
Pregnancy: Pregnancy Category C
Combinations of propranolol and hydrochlorothiazide have not been evaluated for effects on
pregnancy in animals. Nor are there adequate and well-controlled studies of propranolol,
hydrochlorothiazide, or Inderide in pregnant women. Inderide should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Propranolol hydrochloride (Inderal®)
In a series of reproduction and developmental toxicology studies, propranolol was given to rats
by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day
(>30 times the dose of propranolol contained in the maximum recommended human daily dose
of Inderide), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity
(reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths).
Propranolol also was administered (in the feed) to rabbits (throughout pregnancy and lactation)
at doses as high as 150 mg/kg/day (>45 times the dose of propranolol contained in the maximum
recommended daily human dose of Inderide). No evidence of embryo or neonatal toxicity was
noted.
Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported
in human neonates whose mothers received propranolol during pregnancy. Neonates whose
mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia and/or
respiratory depression. Adequate facilities for monitoring these infants at birth should be
available.
8
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hydrochlorothiazide
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats at doses
of up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.
Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant
women requires that the anticipated benefit be weighed against possible hazards to the fetus.
These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse
reactions that have occurred in the adult.
Nursing Mothers
Propranolol hydrochloride (Inderal®)
Propranolol is excreted in human milk. Caution should be exercised when Inderide is
administered to a nursing woman.
Hydrochlorothiazide
Thiazides appear in breast milk. If the use of drug is deemed essential, the patient should stop
nursing.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Inderide did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
The following adverse reactions have been observed, but there is not enough systematic
collection of data to support an estimate of their frequency. Within each category, adverse
reactions are listed in decreasing order of severity. Although many side effects are mild and
transient, some require discontinuation of therapy.
Propranolol hydrochloride (Inderal®)
Cardiovascular: Congestive heart failure; hypotension; intensification of AV block; bradycardia;
thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type; paresthesia of
hands.
Central Nervous System: Reversible mental depression progressing to catatonia; mental
depression manifested by insomnia, lassitude, weakness, fatigue; an acute reversible syndrome
characterized by disorientation for time and place, short-term memory loss, emotional lability,
slightly clouded sensorium, decreased performance on neuropsychometrics; hallucinations;
visual disturbances; vivid dreams; light-headedness. Total daily doses above 160 mg (when
administered as divided doses of greater than 80 mg each) may be associated with an increased
incidence of fatigue, lethargy, and vivid dreams.
9
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis; nausea, vomiting, epigastric
distress, abdominal cramping, diarrhea, constipation.
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions;
laryngospasm and respiratory distress; pharyngitis and agranulocytosis; fever combined with
aching and sore throat; erythematous rash.
Respiratory: Bronchospasm.
Hematologic: Agranulocytosis; nonthrombocytopenic purpura; thrombocytopenic purpura.
Autoimmune: In extremely rare instances, systemic lupus erythematosus has been reported.
Miscellaneous: Male impotence. Alopecia, LE-like reactions, psoriasiform rashes, dry eyes, and
Peyronie's disease have been reported rarely. Oculomucocutaneous reactions involving the skin,
serous membranes, and conjunctivae reported for a beta blocker (practolol) have not been
associated with propranolol.
Skin: Stevens-Johnson Syndrome; toxic epidermal necrolysis; exfoliative dermatitis; erythema
multiforme; urticaria.
Hydrochlorothiazide
Cardiovascular: Orthostatic hypotension (may be aggravated by alcohol, barbiturates or
narcotics).
Central Nervous System: Dizziness, vertigo, headache, xanthopsia, paresthesias.
Gastrointestinal: Pancreatitis; jaundice (intrahepatic cholestatic jaundice); sialadenitis; anorexia,
nausea, vomiting, gastric irritation, cramping, diarrhea, constipation.
Hypersensitivity: Anaphylactic reactions; necrotizing angiitis (vasculitis, cutaneous vasculitis);
respiratory distress including pneumonitis; fever; urticaria, rash, purpura, photosensitivity.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis
including toxic epidermal necrolysis.
Miscellaneous: Hyperglycemia, glycosuria; hyperuricemia; muscle spasm; weakness;
restlessness; transient blurred vision.
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or
therapy withdrawn.
OVERDOSAGE
The propranolol hydrochloride component may cause bradycardia, cardiac failure, hypotension,
or bronchospasm. Propranolol is not significantly dialyzable.
10
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The hydrochlorothiazide component can be expected to cause diuresis. Lethargy of varying
degree may appear and may progress to coma within a few hours, with minimal depression of
respiration and cardiovascular function, and in the absence of significant serum electrolyte
changes or dehydration. The mechanism of central nervous system depression with thiazide
overdosage is unknown. Gastrointestinal irritation and hypermotility can occur, temporary
elevation of BUN has been reported, and serum electrolyte changes could occur, especially in
patients with impairment of renal function.
The oral LD50 dosages in rats and mice for propranolol, hydrochlorothiazide, and combined
propranolol/hydrochlorothiazide (40/25, 80/25) are 364 to 533 mg/kg, greater than
2,750 to 5,000 mg/kg, and 538 to 845 mg/kg, respectively.
Treatment
The following measures should be employed:
General—If ingestion is, or may have been, recent, evacuate gastric contents, taking care to
prevent pulmonary aspiration.
Bradycardia—Administer atropine (0.25 to 1.0 mg). If there is no response to vagal blockade,
administer isoproterenol cautiously.
Cardiac Failure—Digitalization and diuretics.
Hypotension—Vasopressors, e.g., levarterenol or epinephrine.
Bronchospasm—Administer isoproterenol and aminophylline.
Stupor or Coma—Administer supportive therapy as clinically warranted.
Gastrointestinal Effects—Though usually of short duration, these may require symptomatic
treatment.
Abnormalities in BUN and/or Serum Electrolytes—Monitor serum electrolyte levels and renal
function; institute supportive measures as required individually to maintain hydration, electrolyte
balance, respiration, and cardiovascular-renal function.
DOSAGE AND ADMINISTRATION
The dosage must be determined by individual titration.
Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. The initial
dose of propranolol is 80 mg daily, and it may be increased gradually until optimal blood
pressure control is achieved. The usual effective dose when used alone is 160 to 480 mg per day.
One Inderide Tablet twice daily can be used to administer up to 160 mg of propranolol and
50 mg of hydrochlorothiazide. For doses of propranolol greater than 160 mg the combination
products are not appropriate, because their use would lead to an excessive dose of the thiazide
component.
11
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
c
ompany logo
When necessary, another antihypertensive agent may be added gradually beginning with
50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure.
HOW SUPPLIED
Inderide 40/25
Each hexagonal-shaped, off-white, scored tablet, embossed with an “I” and imprinted with
“INDERIDE 40/25,” contains 40 mg propranolol hydrochloride (Inderal®) and 25 mg
hydrochlorothiazide, in bottles of 100 (NDC 24090-484-88).
Inderide 80/25
Each hexagonal-shaped, off-white, scored tablet, embossed with an “I” and imprinted with
“INDERIDE 80/25,” contains 80 mg propranolol hydrochloride (Inderal®) and 25 mg
hydrochlorothiazide, in bottles of 100 (NDC 24090-488-88).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°-30°C (59°-86°C). [See USP
Controlled Room Temperature]
Protect from moisture, freezing, and excessive heat.
Dispense in a well-closed container as defined in the USP.
The appearance of these tablets is a registered trademark of Wyeth Pharmaceuticals.
This product’s label may have been updated. For current package insert and
further product information, call our medical communications department
toll-free at 888‐383 1733
.
Manufactured for Akrimax Pharmaceuticals, LLC
Cranford, NJ 07016
By Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
(Update 248F402)
RevDate 01/2011
12
Reference ID: 2919393
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:30.933281
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018031s037s038lbl.pdf', 'application_number': 18031, 'submission_type': 'SUPPL ', 'submission_number': 38}
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NDA 18-008/ S-066, 18-037/ S-066, 19-308/ S-023
Page 3
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-008/ S-066, 18-037/ S-066, 19-308/ S-023
Page 4
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
The flexible container is made with non-latex plastic materials specially designed for a wide range of
parenteral drugs including those requiring delivery in containers made of polyolefins or polypropylene.
For example, the AVIVA container system is compatible with and appropriate for use in the admixture
and administration of paclitaxel. In addition, the AVIVA container system is compatible with and
appropriate for use in the admixture and administration of all drugs deemed compatible with existing
polyvinyl chloride container systems. The solution contact materials do not contain PVC, DEHP, or
other plasticizers.
The suitability of the container materials has been established through biological evaluations, which
have shown the container passes Class VI U.S. Pharmacopeia (USP) testing for plastic containers.
These tests confirm the biological safety of the container system.
The flexible container is a closed system, and air is prefilled in the container to facilitate drainage. The
container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an intravenous
administration set and the other port has a medication site for addition of supplemental medication
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-008/ S-066, 18-037/ S-066, 19-308/ S-023
Page 5
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series connections. Such use
could result in air embolism due to residual air being drawn from one container before administration
of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase flow rates can
result in air embolism if the residual air in the container is not fully evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could result in air
embolism. Vented intravenous administration sets with the vent in the open position should not be
used with flexible plastic containers.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid
balance, electrolyte concentrations, and acid base balance during prolonged parenteral therapy or
whenever the condition of the patient warrants such evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-008/ S-066, 18-037/ S-066, 19-308/ S-023
Page 6
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in the
responses between elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-008/ S-066, 18-037/ S-066, 19-308/ S-023
Page 7
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Reactions which may occur because of the solution or the technique of administration include febrile
response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of
injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate
therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Do not administer unless solution is clear and seal is intact.Use of a final filter is recommended during
administration of all parenteral solutions, where possible.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
Additives may be incompatible. Complete information is not available. Those additives known to be
incompatible should not be used. Consult with pharmacist, if available. If, in the informed judgment
of the physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly
when additives have been introduced. Do not store solutions containing additives.
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-008/ S-066, 18-037/ S-066, 19-308/ S-023
Page 8
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
If supplemental medication is desired, follow directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-008/ S-066, 18-037/ S-066, 19-308/ S-023
Page 9
3. Mix solution and medication thoroughly. For high density medication such as potassium chloride,
squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
07-19-50-548
Rev. April 2006
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018008s066,018037s066,019308s023lbl.pdf', 'application_number': 18037, 'submission_type': 'SUPPL ', 'submission_number': 66}
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DESCRIPTION
Estramustine phosphate sodium, an antineoplastic agent, is an off-white powder
readily soluble in water. EMCYT Capsules are white and opaque, each containing
estramustine phosphate sodium as the disodium salt monohydrate equivalent to
140 mg estramustine phosphate, for oral administration. Each capsule also contains
magnesium stearate, silicon dioxide, sodium lauryl sulfate, and talc. Gelatin capsule
shells contain the following pigment: titanium dioxide.
Chemically, estramustine phosphate sodium is estra-1,3,5(10)-triene-3,17-diol(17ß)-,
3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate.
It is also referred to as estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen
phosphate), disodium salt, monohydrate.
Estramustine phosphate sodium has an empiric formula of C23H30Cl2NNa2O6P•H2O,
a calculated molecular weight of 582.4, and the following structural formula:
CLINICAL PHARMACOLOGY
Estramustine phosphate (Figure 1) is a molecule combining estradiol and nornitrogen
mustard by a carbamate link. The molecule is phosphorylated to make it water
soluble.
Figure 1. Estramustine Phosphate
Estramustine phosphate taken orally is readily dephosphorylated during absorption,
and the major metabolites in plasma are estramustine (Figure 2), the estrone analog
(Figure 3), estradiol, and estrone.
Figure 2. Estramustine
Figure 3. Estrone Analog of Estramustine
Prolonged treatment with estramustine phosphate produces elevated total plasma
concentrations of estradiol that fall within ranges similar to the elevated estradiol
levels found in prostatic cancer patients given conventional estradiol therapy.
Estrogenic effects, as demonstrated by changes in circulating levels of steroids and
pituitary hormones, are similar in patients treated with either estramustine phosphate
or conventional estradiol.
The metabolic urinary patterns of the estradiol moiety of estramustine phosphate
and estradiol itself are very similar, although the metabolites derived from estramustine
phosphate are excreted at a slower rate.
N—C—O
O
CICH2CH2
CICH2CH2
ONa
ONa
O—P
O
• H2O
N—C—O
O
CICH2CH2
CICH2CH2
OH
OH
O—P
O
N—C—O
O
CICH2CH2
CICH2CH2
O
N—C—O
O
CICH2CH2
CICH2CH2
OH
Emcyt
®
estramustine phosphate sodium
capsules
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Layout and/or size adjusted for
ease of reading and printing.
INDICATIONS AND USAGE
EMCYT Capsules are indicated in the palliative treatment of patients with metastatic
and/or progressive carcinoma of the prostate.
CONTRAINDICATIONS
EMCYT Capsules should not be used in patients with any of the following conditions:
1) Known hypersensitivity to either estradiol or to nitrogen mustard.
2) Active thrombophlebitis or thromboembolic disorders, except in those cases
where the actual tumor mass is the cause of the thromboembolic phenomenon
and the physician feels the benefits of therapy may outweigh the risks.
WARNINGS
It has been shown that there is an increased risk of thrombosis, including fatal and
nonfatal myocardial infarction, in men receiving estrogens for prostatic cancer.
EMCYT Capsules should be used with caution in patients with a history of
thrombophlebitis, thrombosis, or thromboembolic disorders, especially if they were
associated with estrogen therapy. Caution should also be used in patients with
cerebral vascular or coronary artery disease.
Glucose Tolerance—Because glucose tolerance may be decreased, diabetic patients
should be carefully observed while receiving EMCYT.
Elevated Blood Pressure—Because hypertension may occur, blood pressure should
be monitored periodically.
PRECAUTIONS
General
Fluid Retention. Exacerbation of preexisting or incipient peripheral edema or
congestive heart disease has been seen in some patients receiving therapy with
EMCYT Capsules. Other conditions which might be influenced by fluid retention,
such as epilepsy, migraine, or renal dysfunction, require careful observation.
EMCYT may be poorly metabolized in patients with impaired liver function and
should be administered with caution in such patients.
Because EMCYT may influence the metabolism of calcium and phosphorus, it
should be used with caution in patients with metabolic bone diseases that are
associated with hypercalcemia or in patients with renal insufficiency.
Gynecomastia and impotence are known estrogenic effects.
Allergic reactions and angioedema at times involving the airway have been reported.
Information for the Patient
Because of the possibility of mutagenic effects, patients should be advised to use
contraceptive measures.
Laboratory Tests
Certain endocrine and liver function tests may be affected by estrogen-containing
drugs. EMCYT may depress testosterone levels. Abnormalities of hepatic enzymes
and of bilirubin have occurred in patients receiving EMCYT. Such tests should be
done at appropriate intervals during therapy and repeated after the drug has been
withdrawn for two months.
Food/Drug Interaction
Milk, milk products, and calcium-rich foods or drugs may impair the absorption of
EMCYT.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of estrogens in certain animal species increases
the frequency of carcinomas of the breast and liver. Compounds structurally similar
to EMCYT are carcinogenic in mice. Carcinogenic studies of EMCYT have not been
conducted in man. Although testing by the Ames method failed to demonstrate
mutagenicity for estramustine phosphate sodium, it is known that both estradiol
and nitrogen mustard are mutagenic. For this reason and because some patients
who had been impotent while on estrogen therapy have regained potency while
taking EMCYT, the patient should be advised to use contraceptive measures.
100002341.00.9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients with prostate cancer and
osteoblastic metastases are at risk
for hypocalcemia and should have
calcium levels closely monitored.
ADVERSE REACTIONS
In a randomized, double-blind trial comparing therapy with EMCYT Capsules in
93 patients (11.5 to 15.9 mg/kg/day) or diethylstilbestrol (DES) in 93 patients
(3.0 mg/day), the following adverse effects were reported:
EMCYT
DES
n=93
n=93
CARDIOVASCULAR-RESPIRATORY
Cardiac Arrest
0
2
Cerebrovascular Accident
2
0
Myocardial Infarction
3
1
Thrombophlebitis
3
7
Pulmonary Emboli
2
5
Congestive Heart Failure
3
2
Edema
19
17
Dyspnea
11
3
Leg Cramps
8
11
Upper Respiratory Discharge
1
1
Hoarseness
1
0
GASTROINTESTINAL
Nausea
15
8
Diarrhea
12
11
Minor Gastrointestinal Upset
11
6
Anorexia
4
3
Flatulence
2
0
Vomiting
1
1
Gastrointestinal Bleeding
1
0
Burning Throat
1
0
Thirst
1
0
INTEGUMENTARY
Rash
1
4
Pruritus
2
2
Dry Skin
2
0
Pigment Changes
0
3
Easy Bruising
3
0
Flushing
1
0
Night Sweats
0
1
Fingertip—Peeling Skin
1
0
Thinning Hair
1
1
BREAST CHANGES
Tenderness
66
64
Enlargement
Mild
60
54
Moderate
10
16
Marked
0
5
MISCELLANEOUS
Lethargy Alone
4
3
Depression
0
2
Emotional Lability
2
0
Insomnia
3
0
Headache
1
1
Anxiety
1
0
Chest Pain
1
1
Hot Flashes
0
1
Pain in Eyes
0
1
Tearing of Eyes
1
1
Tinnitus
0
1
LABORATORY ABNORMALITIES
Hematologic
Leukopenia
4
2
Thrombopenia
1
2
Hepatic
Bilirubin Alone
1
5
Bilirubin and LDH
0
1
Bilirubin and SGOT
2
1
Bilirubin, LDH and SGOT
2
0
LDH and/or SGOT
31
28
Miscellaneous
Hypercalcemia—Transient
0
1
OVERDOSAGE
Although there has been no experience with overdosage to date, it is reasonable
to expect that such episodes may produce pronounced manifestations of the known
adverse reactions. In the event of overdosage, the gastric contents should be
evacuated by gastric lavage and symptomatic therapy should be initiated. Hematologic
and hepatic parameters should be monitored for at least 6 weeks after overdosage
of EMCYT Capsules.
Emcyt
brand of estramustine phosphate sodium capsules
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
The recommended daily dose is 14 mg per kg of body weight (ie, one 140 mg
capsule for each 10 kg or 22 lb of body weight), given in 3 or 4 divided doses. Most
patients in studies in the United States have been treated at a dosage range of 10
to 16 mg per kg per day.
Patients should be instructed to take EMCYT Capsules at least 1 hour before or
2 hours after meals. EMCYT should be swallowed with water. Milk, milk products, and
calcium-rich foods or drugs (such as calcium-containing antacids) must not be taken
simultaneously with EMCYT.
Patients should be treated for 30 to 90 days before the physician determines the
possible benefits of continued therapy. Therapy should be continued as long as the
favorable response lasts. Some patients have been maintained on therapy for more
than 3 years at doses ranging from 10 to 16 mg per kg of body weight per day.
Procedures for proper handling and disposal of anticancer drugs should be
considered. Several guidelines on this subject have been published.1-8 There is no
general agreement that all of the procedures recommended in the guidelines are
necessary or appropriate.
HOW SUPPLIED
White opaque capsules, each containing estramustine phosphate sodium as the
disodium salt monohydrate equivalent to 140 mg estramustine phosphate—bottle
of 100 (NDC 0013-0132-02).
NOTE
EMCYT Capsules should be stored at 36° to 46°F (2° to 8°C).
REFERENCES
1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH
Publication No. 83-2621. For sale by the Superintendent of Documents, U.S.
Government Printing Office, Washington, DC, 20402.
2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA.
1985; 253 (11):1590-1592.
3. National Study Commission on Cytotoxic Exposure-Recommendations for
Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman,
National Study Commission on Cytotoxic Exposure, Massachusetts College of
Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston,
Massachusetts 02115.
4. Clinical Oncological Society of Australia. Guidelines and Recommendations for
Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426-428.
5. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the
Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians. 1983; (Sept/Oct)
258-263.
6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling
Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049.
7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic)
Drugs. Am J Hosp Pharm. 1986; 43:1193-1204.
8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and
Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society;
1999:32-41.
Manufactured for: Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, MI 49001, USA
by: Pharmacia Italia S.p.A.
Ascoli Piceno, Italy
Revised: February 2002
819 171 000
100002341.00.9
only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
March 2003
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18045slr021_emcyt_lbl.pdf', 'application_number': 18045, 'submission_type': 'SUPPL ', 'submission_number': 21}
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07-19-69-877
Baxter
Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP
in Plastic Container
VIAFLEX Plus Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile,
nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. It contains no antimicrobial agents.
Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table
1.
Table 1
Potassium Chloride
in 5% Dextrose and
0.2% Sodium
Chloride Injection,
USP
mEq Potassium
Size (mL)
Composition (g/L)
* Osmolarity (mOsmol/L)
(calc.)
pH
Ionic Concentration
(mEq/L)
Caloric Content (kCal/L)
**Dextrose Hydrous, USP
Sodium Chloride, USP (NaCl)
Potassium Chloride, USP (KCl)
Sodium
Potassium
Chloride
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
1
Reference ID: 3370955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Potassium Chloride
in 5% Dextrose and
0.33% Sodium
Chloride Injection,
USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride
in 5% Dextrose and
0.45% Sodium
Chloride Injection,
USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride
in 5% Dextrose and
0.9% Sodium
Chloride Injection,
USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
2
Reference ID: 3370955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
The VIAFLEX Plus plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). VIAFLEX Plus on the container indicates the presence of a
drug additive in a drug vehicle. The VIAFLEX Plus plastic container system utilizes the
same container as the VIAFLEX plastic container system. The amount of water that can
permeate from inside the container into the overwrap is insufficient to affect the solution
significantly. Solutions in contact with the plastic container can leach out certain of its
chemical components in very small amounts within the expiration period, e.g., di-2
ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic
has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a
source of water, electrolytes and calories. It is capable of inducing diuresis depending on
the clinical condition of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a
source of water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to
corn or corn products.
Warnings
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used
with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
3
Reference ID: 3370955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used
with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be
administered simultaneously with blood through the same administration set because of
the possibility of pseudoagglutination or hemolysis. The container label for these
injections bears the statement: Do not administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration, congested states or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of
the injection. The risk of solute overload causing congested states with peripheral and
pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Potassium Chloride in 5%
Dextrose and Sodium Chloride Injection, USP may result in sodium or potassium
retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection
may result in increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
Do not use plastic containers in series connections. Such use could result in air embolism
due to residual air being drawn from the primary container before administration of the
fluid from the secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
4
Reference ID: 3370955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical evaluation and periodic laboratory determinations are necessary to monitor
changes in fluid balance, electrolyte concentrations, and acid base balance during
prolonged parenteral therapy or whenever the condition of the patient warrants such
evaluation.
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose
and Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used
with caution in patients with overt or subclinical diabetes mellitus.
The osmolarity of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP ranges from 341 to 641 mOsmol/L (calc). Administration of hypertonic solutions
may cause venous irritation, including phlebitis. Hyperosmolar solutions should be
administered with caution, if at all, to patients with hyperosmolar states.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP
have not been performed to evaluate carcinogenic potential, mutagenic potential or
effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not
known whether Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP
can cause fetal harm when administered to a pregnant woman or can affect reproduction
capacity. Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP
should be given to a pregnant woman only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when Potassium Chloride in 5%
Dextrose and Sodium Chloride Injection, USP is administered to a nursing mother.
For patients receiving potassium supplement at greater than maintenance rates, frequent
monitoring of serum potassium levels and serial EKGs are recommended.
Do not administer unless solution is clear and seal is intact.
Reference ID: 3370955
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
The use of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients is based on clinical practice.
Newborns – especially those born premature and with low birth weight - are at increased
risk of developing hypo- or hyperglycemia and therefore need close monitoring during
treatment with intravenous glucose solutions to ensure adequate glycemic control in order
to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause
prolonged seizures, coma and brain damage. Hyperglycemia has been associated with
intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of
prematurity, necrotizing enterocolitits, bronchopulmonary dysplasia, prolonged length of
hospital stay, and death.
Plasma electrolyte concentrations should be closely monitored in the pediatric population
as this population may have impaired ability to regulate fluids and electrolytes.
The infusion of hypotonic fluids together with the non-osmotic secretion of ADH may
result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to
headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute
symptomatic hyponatremic encephalopathy is considered a medical emergency (applies
to solutions containing less than 0.9% Sodium Chloride Injection).
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Adverse Reactions
- Hypersensitivity reactions, including anaphylaxis and chills
- Hyponatremia (applies to solutions containing less than 0.9% Sodium Chloride)
6
Reference ID: 3370955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reactions which may occur because of the solution or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis or phlebitis
extending from the site of injection, extravasation, and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures, and save the remainder of the fluid for
examination if deemed necessary.
Dosage and Administration
As directed by a physician. Dosage is dependent upon the age, weight and clinical
condition of the patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Use of a
final filter is recommended during administration of all parenteral solutions, where
possible.
All injections in VIAFLEX Plus plastic containers are intended for intravenous
administration using sterile equipment.
The dosage selection and constant infusion rate of intravenous dextrose must be selected
with caution in pediatric patients, particularly neonates and low birth weight infants,
because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of
serum glucose concentrations is required when dextrose is prescribed to pediatric
patients, particularly neonates and low birth weight infants. The infusion rate and
volume depends on the age, weight, clinical and metabolic conditions of the patient,
concomitant therapy and should be determined by the consulting physician experienced
in pediatric intravenous fluid therapy.
Additives may be incompatible. Complete information is not available. Those additives
known to be incompatible should not be used. Consult with pharmacist, if available. If, in
the informed judgment of the physician, it is deemed advisable to introduce additives, use
aseptic technique. Mix thoroughly when additives have been introduced. Do not store
solutions containing additives.
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in VIAFLEX
Plus plastic container is available as follows:
7
Reference ID: 3370955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Code
Size (mL)
NDC
Product Name
2B1604
1000
0338-0661-04
10 mEq/L Potassium Chloride in 5% Dextrose and
0.2% Sodium Chloride Injection, USP
2B1614
1000
0338-0663-04
20 mEq/L Potassium Chloride in 5% Dextrose and
2B1613
500
0.2% Sodium Chloride Injection, USP
0338-0663-03
2B1624
1000
0338-0665-04
30 mEq/L Potassium Chloride in 5% Dextrose and
0.2% Sodium Chloride Injection, USP
2B1634
1000
0338-0667-04
40 mEq/L Potassium Chloride in 5% Dextrose and
0.2% Sodium Chloride Injection, USP
2B1474
1000
0338-0603-04
20 mEq/L Potassium Chloride in 5% Dextrose and
2B1473
500
0338-0603-03
0.33% Sodium Chloride Injection, USP
2B1484
1000
0338-0605-04
30 mEq/L Potassium Chloride in 5% Dextrose and
0.33% Sodium Chloride Injection, USP
2B1494
1000
0338-0607-04
40 mEq/L Potassium Chloride in 5% Dextrose and
0.33% Sodium Chloride Injection, USP
2B1644
1000
0338-0669-04
10 mEq/L Potassium Chloride in 5% Dextrose and
0.45% Sodium Chloride Injection, USP
2B1654
1000
0338-0671-04
20 mEq/L Potassium Chloride in 5% Dextrose and
2B1653
500
0338-0671-03
0.45% Sodium Chloride Injection, USP
2B1664
1000
0338-0673-04
30 mEq/L Potassium Chloride in 5% Dextrose and
0.45% Sodium Chloride Injection, USP
2B1674
1000
0338-0675-04
40 mEq/L Potassium Chloride in 5% Dextrose and
0.45% Sodium Chloride Injection, USP
2B2434
1000
0338-0803-04
20 mEq/L Potassium Chloride in 5% Dextrose and
0.9% Sodium Chloride Injection, USP
2B2454
1000
0338-0807-04
40 mEq/L Potassium Chloride in 5% Dextrose and
0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C); brief exposure up to
40°C does not adversely affect the product.
Directions for Use of VIAFLEX Plus Plastic Container
For Information on Risk of Air Embolism – see Precautions
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This
is normal and does not affect the solution quality or safety. The opacity will diminish
8
Reference ID: 3370955
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found,
discard solution as sterility may be impaired. If supplemental medication is desired,
follow directions below.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Warning: Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright
position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
Reference ID: 3370955
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Distributed in Canada by
Baxter Corporation
Mississauga, ON L5N 0C2
*For Bar Code Position Only
071969877
07-19-69-877
Rev. September 2013
Baxter, PL 146, and Viaflex are trademarks of
Baxter International Inc.
Reference ID: 3370955
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:31.279523
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018008s070,018037s070,019308s027lbl.pdf', 'application_number': 18037, 'submission_type': 'SUPPL ', 'submission_number': 70}
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11,133
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Emcyt®
estramustine phosphate sodium
capsules
DESCRIPTION
Estramustine phosphate sodium, an antineoplastic agent, is an off-white powder readily
soluble in water. EMCYT Capsules are white and opaque, each containing estramustine
phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine
phosphate, for oral administration. Each capsule also contains magnesium stearate,
silicon dioxide, sodium lauryl sulfate, and talc. Gelatin capsule shells contain the
following pigment: titanium dioxide.
Chemically, estramustine phosphate sodium is estra-1,3,5(10)-triene-3,17-diol(17ß)-,3
[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate.
It is also referred to as estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen
phosphate), disodium salt, monohydrate.
Estramustine phosphate sodium has an empiric formula of C23H30Cl2NNa2O6P•H2O, a
calculated molecular weight of 582.4, and the following structural formula: Chemical Structure
CLINICAL PHARMACOLOGY
Estramustine phosphate (Figure 1) is a molecule combining estradiol and nornitrogen
mustard by a carbamate link. The molecule is phosphorylated to make it water soluble.
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Chemical Structure
Estramustine phosphate taken orally is readily dephosphorylated during absorption, and
the major metabolites in plasma are estramustine (Figure 2), the estrone analog (Figure
3), estradiol, and estrone. Chemical Structure
Prolonged treatment with estramustine phosphate produces elevated total plasma
concentrations of estradiol that fall within ranges similar to the elevated estradiol levels
found in prostatic cancer patients given conventional estradiol therapy. Estrogenic
effects, as demonstrated by changes in circulating levels of steroids and pituitary
hormones, are similar in patients treated with either estramustine phosphate or
conventional estradiol.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and
estradiol itself are very similar, although the metabolites derived from estramustine
phosphate are excreted at a slower rate.
INDICATIONS AND USAGE
EMCYT Capsules are indicated in the palliative treatment of patients with metastatic
and/or progressive carcinoma of the prostate.
CONTRAINDICATIONS
EMCYT Capsules should not be used in patients with any of the following conditions:
1) Known hypersensitivity to either estradiol or to nitrogen mustard.
2) Active thrombophlebitis or thromboembolic disorders, except in those cases
where the actual tumor mass is the cause of the thromboembolic phenomenon and
the physician feels the benefits of therapy may outweigh the risks.
WARNINGS
It has been shown that there is an increased risk of thrombosis, including fatal and
nonfatal myocardial infarction, in men receiving estrogens for prostatic cancer. EMCYT
Capsules should be used with caution in patients with a history of thrombophlebitis,
thrombosis, or thromboembolic disorders, especially if they were associated with
estrogen therapy. Caution should also be used in patients with cerebral vascular or
coronary artery disease.
Glucose Tolerance—Because glucose tolerance may be decreased, diabetic patients
should be carefully observed while receiving EMCYT.
Elevated Blood Pressure—Because hypertension may occur, blood pressure should be
monitored periodically.
PRECAUTIONS
General
Fluid Retention. Exacerbation of preexisting or incipient peripheral edema or congestive
heart disease has been seen in some patients receiving therapy with EMCYT Capsules.
Other conditions which might be influenced by fluid retention, such as epilepsy,
migraine, or renal dysfunction, require careful observation.
EMCYT may be poorly metabolized in patients with impaired liver function and should
be administered with caution in such patients.
Because EMCYT may influence the metabolism of calcium and phosphorus, it should be
used with caution in patients with metabolic bone diseases that are associated with
hypercalcemia or in patients with renal insufficiency. Patients with prostate cancer and
osteoblastic metastases are at risk for hypocalcemia and should have calcium levels
closely monitored.
Gynecomastia and impotence are known estrogenic effects.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Allergic reactions and angioedema at times involving the airway have been reported.
Information for the Patient
Because of the possibility of mutagenic effects, patients should be advised to use
contraceptive measures.
Laboratory Tests
Certain endocrine and liver function tests may be affected by estrogen-containing drugs.
EMCYT may depress testosterone levels. Abnormalities of hepatic enzymes and of
bilirubin have occurred in patients receiving EMCYT. Such tests should be done at
appropriate intervals during therapy and repeated after the drug has been withdrawn for
two months.
Food/Drug Interaction
Milk, milk products, and calcium-rich foods or drugs may impair the absorption of
EMCYT.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term continuous administration of estrogens in certain animal species increases the
frequency of carcinomas of the breast and liver. Compounds structurally similar to
EMCYT are carcinogenic in mice. Carcinogenic studies of EMCYT have not been
conducted in man. Although testing by the Ames method failed to demonstrate
mutagenicity for estramustine phosphate sodium, it is known that both estradiol and
nitrogen mustard are mutagenic. For this reason and because some patients who had been
impotent while on estrogen therapy have regained potency while taking EMCYT, the
patient should be advised to use contraceptive measures.
ADVERSE REACTIONS
In a randomized, double-blind trial comparing therapy with EMCYT Capsules in 93
patients (11.5 to 15.9 mg/kg/day) or diethylstilbestrol (DES) in 93 patients (3.0 mg/day),
the following adverse effects were reported:
EMCYT
DES
n=93
n=93
CARDIOVASCULAR-RESPIRATORY
Cardiac Arrest
0
2
Cerebrovascular Accident
2
0
Myocardial Infarction
3
1
Thrombophlebitis
3
7
Pulmonary Emboli
2
5
Congestive Heart Failure
3
2
Edema
19
17
Dyspnea
11
3
Leg Cramps
8
11
Upper Respiratory Discharge
1
1
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hoarseness
1
0
GASTROINTESTINAL
Nausea
15
8
Diarrhea
12
11
Minor Gastrointestinal Upset
11
6
Anorexia
4
3
Flatulence
2
0
Vomiting
1
1
Gastrointestinal Bleeding
1
0
Burning Throat
1
0
Thirst
1
0
INTEGUMENTARY
Rash
1
4
Pruritus
2
2
Dry Skin
2
0
Pigment Changes
0
3
Easy Bruising
3
0
Flushing
1
0
Night Sweats
0
1
Fingertip—Peeling Skin
1
0
Thinning Hair
1
1
BREAST CHANGES
Tenderness
66
64
Enlargement
Mild
60
54
Moderate
10
16
Marked
0
5
MISCELLANEOUS
Lethargy Alone
4
3
Depression
0
2
Emotional Lability
2
0
Insomnia
3
0
Headache
1
1
Anxiety
1
0
Chest Pain
1
1
Hot Flashes
0
1
Pain in Eyes
0
1
Tearing of Eyes
1
1
Tinnitus
0
1
LABORATORY ABNORMALITIES
Hematologic
Leukopenia
4
2
Thrombopenia
1
2
Hepatic
Bilirubin Alone
1
5
Bilirubin and LDH
0
1
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Bilirubin and SGOT
Bilirubin, LDH and SGOT
LDH and/or SGOT
Miscellaneous
Hypercalcemia—Transient
2
2
31
0
1
0
28
1
OVERDOSAGE
Although there has been no experience with overdosage to date, it is reasonable to expect
that such episodes may produce pronounced manifestations of the known adverse
reactions. In the event of overdosage, the gastric contents should be evacuated by gastric
lavage and symptomatic therapy should be initiated. Hematologic and hepatic parameters
should be monitored for at least 6 weeks after overdosage of EMCYT Capsules.
DOSAGE AND ADMINISTRATION
The recommended daily dose is 14 mg per kg of body weight (ie, one 140 mg capsule for
each 10 kg or 22 lb of body weight), given in 3 or 4 divided doses. Most patients in
studies in the United States have been treated at a dosage range of 10 to 16 mg per kg per
day.
Patients should be instructed to take EMCYT Capsules at least 1 hour before or 2 hours
after meals. EMCYT should be swallowed with water. Milk, milk products, and calcium-
rich foods or drugs (such as calcium-containing antacids) must not be taken
simultaneously with EMCYT.
Patients should be treated for 30 to 90 days before the physician determines the possible
benefits of continued therapy. Therapy should be continued as long as the favorable
response lasts. Some patients have been maintained on therapy for more than 3 years at
doses ranging from 10 to 16 mg per kg of body weight per day.
Procedures for proper handling and disposal of anticancer drugs should be considered.
Several guidelines on this subject have been published.1–8 There is no general agreement
that all of the procedures recommended in the guidelines are necessary or appropriate.
HOW SUPPLIED
White opaque capsules, each containing estramustine phosphate sodium as the disodium
salt monohydrate equivalent to 140 mg estramustine phosphate—bottle of 100 (NDC
0013-0132-02).
NOTE
EMCYT Capsules should be stored in the refrigerator at 36° to 46°F (2° to 8°C).
REFERENCES
1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH
Publication No. 83–2621. For sale by the Superintendent of Documents, U.S.
Government Printing Office, Washington, DC, 20402.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics,
JAMA. 1985; 253 (11):1590–1592.
3. National Study Commission on Cytotoxic Exposure-Recommendations for
Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman,
National Study Commission on Cytotoxic Exposure, Massachusetts College of
Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston,
Massachusetts 02115.
4. Clinical Oncological Society of Australia. Guidelines and Recommendations for
Safe Handling of Antineoplastic Agents. Med J Australia. 1983; 1:426–428.
5. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the
Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians. 1983;
(Sept/Oct) 258–263.
6. American Society of Hospital Pharmacists Technical Assistance Bulletin on
Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033–
1049.
7. OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic
(Antineoplastic) Drugs. Am J Hosp Pharm. 1986; 43:1193–1204.
8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and
Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society;
1999:32–41.
Pfizer Log & Address
LAB-0088-4.0
Revised June 2007
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:44:31.307243
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018045s023lbl.pdf', 'application_number': 18045, 'submission_type': 'SUPPL ', 'submission_number': 23}
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11,134
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Bupivacaine Hydrochloride
Injection, USP
Bupivacaine Hydrochloride
and Epinephrine
Injection, USP
Rx only
DESCRIPTION
Bupivacaine
Hydrochloride
is
2-Piperidinecarboxamide,
1-butyl-N-(2,6-dimethylphenyl)-,
monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol,
soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: structural formula
Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol. It has the following structural
formula: structural formula
Bupivacaine Hydrochloride is available in sterile isotonic solutions with and without epinephrine (as
bitartrate) 1:200,000 for injection via local infiltration, peripheral nerve block, and caudal and lumbar
epidural blocks. Solutions of Bupivacaine Hydrochloride may be autoclaved if they do not contain
epinephrine. Solutions are clear and colorless.
Bupivacaine is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a
homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an
amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this
respect from the procaine-type local anesthetics, which have an ester linkage.
Bupivacaine Hydrochloride Injection, USP is available in sterile, isotonic solutions containing
bupivacaine hydrochloride in water for injection with characteristics as follows:
Bupivacaine Hydrochloride Injection, USP
(without epinephrine)
Bupivacaine Hydrochloride
Sodium Chloride
Concentration
mg/mL
mg/mL
0.25%
2.5
8.6
0.5%
5
8.1
0.75%
7.5
7.6
May contain sodium hydroxide and/or hydrochloric acid for pH adjustment. (See HOW SUPPLIED
section for pH information.) Multiple-dose vials contain methylparaben 1 mg/mL added as a preservative.
wEN-3182v04
Page 1 of 14
Reference ID: 3790419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Bupivacaine and Epinephrine Injection, USP is available in sterile, isotonic solutions containing
bupivacaine hydrochloride and epinephrine 1:200,000 with characteristics as follows:
Bupivacaine and Epinephrine Injection, USP
Bupivacaine
Epinephrine
Sodium
Concentration
Hydrochloride
1:200,000
Chloride
(Bupivacaine HCl)
(mg/mL)
(mcg/mL)
(mg/mL)
0.25%
2.5
5
8.5
0.5%
5
5
8.5
0.75%
7.5
5
8.5
Sodium metabisulfite 0.1 mg/mL added as antioxidant and edetate calcium disodium, anhydrous
0.1 mg/mL added as stabilizer. May contain sodium hydroxide and/or hydrochloric acid for pH
adjustment. (See HOW SUPPLIED section for pH information.) Multiple-dose vials contain
methylparaben 1 mg/mL added as a preservative.
Single-dose solutions contain no added bacteriostat or anti-microbial agent and unused portions
should be discarded after use.
CLINICAL PHARMACOLOGY
Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing
the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and
by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to
the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of
nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal
muscle tone.
Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous
systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac
conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.
However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to
atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In
addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased
cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these
cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine.
Therefore, incremental dosing is necessary.
Following systemic absorption, local anesthetics can produce central nervous system stimulation,
depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering
progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest.
However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The
depressed stage may occur without a prior excited state.
Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose
and concentration of drug administered, the route of administration, the vascularity of the administration
site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of
epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma
concentration of Bupivacaine Hydrochloride, permitting the use of moderately larger total doses and
sometimes prolonging the duration of action.
The onset of action with Bupivacaine Hydrochloride is rapid and anesthesia is long lasting. The
duration of anesthesia is significantly longer with Bupivacaine Hydrochloride than with any other
commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after
the return of sensation, during which time the need for strong analgesics is reduced.
wEN-3182v04
Page 2 of 14
Reference ID: 3790419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma
concentration of drug the higher the percentage of drug bound to plasma proteins.
Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is
governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of
lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of
plasma protein binding, because only the free, unbound drug is available for placental transfer.
Bupivacaine Hydrochloride with a high protein binding capacity (95%) has a low fetal/maternal ratio
(0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid
solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal
circulation.
Depending upon the route of administration, local anesthetics are distributed to some extent to all
body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and
brain.
Pharmacokinetic studies on the plasma profile of Bupivacaine Hydrochloride after direct intravenous
injection suggest a three-compartment open model. The first compartment is represented by the rapid
intravascular distribution of the drug. The second compartment represents the equilibration of the drug
throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third
compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat.
The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the
circulation to carry it to the liver where it is metabolized.
After injection of Bupivacaine Hydrochloride for caudal, epidural, or peripheral nerve block in man,
peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to
insignificant levels during the next three to six hours.
Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the
presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood
flow, the route of drug administration, and the age of the patient. The half-life of Bupivacaine
Hydrochloride in adults is 2.7 hours and in neonates 8.1 hours.
In clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor
blockade more rapidly than younger patients. Elderly patients also exhibited higher peak plasma
concentrations following administration of this product. The total plasma clearance was decreased in these
patients.
Amide-type local anesthetics such as Bupivacaine Hydrochloride are metabolized primarily in the
liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe
hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics.
Pipecoloxylidine is the major metabolite of Bupivacaine Hydrochloride.
The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary
excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is
excreted unchanged in the urine.
When administered in recommended doses and concentrations, Bupivacaine Hydrochloride does not
ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.
INDICATIONS AND USAGE
Bupivacaine Hydrochloride is indicated for the production of local or regional anesthesia or analgesia for
surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical
procedures. Only the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. (See
WARNINGS.)
Experience with nonobstetrical surgical procedures in pregnant patients is not sufficient to recommend
use of 0.75% concentration of Bupivacaine Hydrochloride in these patients.
wEN-3182v04
Page 3 of 14
Reference ID: 3790419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Bupivacaine Hydrochloride is not recommended for intravenous regional anesthesia (Bier Block).
(See WARNINGS.)
The routes of administration and indicated Bupivacaine Hydrochloride concentrations are:
• local infiltration
0.25%
• peripheral nerve block
0.25% and 0.5%
• retrobulbar block
0.75%
• sympathetic block
0.25%
• lumbar epidural
0.25%, 0.5%, and 0.75% (0.75% not for obstetrical anesthesia)
• caudal
0.25% and 0.5%
• epidural test dose
0.5% with epinephrine 1:200,000
(See DOSAGE AND ADMINISTRATION for additional information.)
Standard textbooks should be consulted to determine the accepted procedures and techniques for the
administration of Bupivacaine Hydrochloride.
CONTRAINDICATIONS
Bupivacaine Hydrochloride is contraindicated in obstetrical paracervical block anesthesia. Its use in this
technique has resulted in fetal bradycardia and death.
Bupivacaine Hydrochloride is contraindicated in patients with a known hypersensitivity to it or to any
local anesthetic agent of the amide-type or to other components of Bupivacaine Hydrochloride solutions.
WARNINGS
THE 0.75% CONCENTRATION OF BUPIVACAINE HYDROCHLORIDE IS NOT
RECOMMENDED FOR OBSTETRICAL ANESTHESIA.
THERE
HAVE
BEEN
REPORTS
OF
CARDIAC
ARREST
WITH
DIFFICULT
RESUSCITATION OR DEATH DURING USE OF BUPIVACAINE HYDROCHLORIDE FOR
EPIDURAL ANESTHESIA IN OBSTETRICAL PATIENTS. IN MOST CASES, THIS HAS
FOLLOWED USE OF THE 0.75% CONCENTRATION. RESUSCITATION HAS BEEN
DIFFICULT OR IMPOSSIBLE DESPITE APPARENTLY ADEQUATE PREPARATION AND
APPROPRIATE
MANAGEMENT.
CARDIAC
ARREST
HAS
OCCURRED
AFTER
CONVULSIONS
RESULTING
FROM
SYSTEMIC
TOXICITY,
PRESUMABLY
FOLLOWING
UNINTENTIONAL
INTRAVASCULAR
INJECTION.
THE
0.75%
CONCENTRATION SHOULD BE RESERVED FOR SURGICAL PROCEDURES WHERE A
HIGH DEGREE OF MUSCLE RELAXATION AND PROLONGED EFFECT ARE
NECESSARY.
LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL
VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER
ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND
THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER
RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE
PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS
AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS, PRECAUTIONS, and
OVERDOSAGE.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY,
UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO
THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.
Local anesthetic solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose
vials, should not be used for epidural or caudal anesthesia because safety has not been established with
regard to intrathecal injection, either intentionally or unintentionally, of such preservatives.
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Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an
unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such
infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno
humeral chondrolysis have been described in pediatric and adult patients following intra-articular
infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is
insufficient information to determine whether shorter infusion periods are not associated with these
findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable,
but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for
chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic
procedures and some required arthroplasty or shoulder replacement.
It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to
injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or
subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or
subarachnoid injection.
Bupivacaine Hydrochloride with epinephrine 1:200,000 or other vasopressors should not be used
concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur.
Likewise, solutions of Bupivacaine Hydrochloride containing a vasoconstrictor, such as epinephrine,
should be used with extreme caution in patients receiving monoamineoxidase inhibitors (MAOI) or
antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result.
Until further experience is gained in pediatric patients younger than 12 years, administration of
Bupivacaine Hydrochloride in this age group is not recommended.
Mixing or the prior or intercurrent use of any other local anesthetic with Bupivacaine Hydrochloride
cannot be recommended because of insufficient data on the clinical use of such mixtures. There have been
reports of cardiac arrest and death during the use of Bupivacaine Hydrochloride for intravenous regional
anesthesia (Bier Block). Information on safe dosages and techniques of administration of Bupivacaine
Hydrochloride in this procedure is lacking. Therefore, Bupivacaine Hydrochloride is not recommended
for use in this technique.
Bupivacaine Hydrochloride with epinephrine 1:200,000 contains sodium metabisulfite, a sulfite that
may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe
asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the
general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic
than in nonasthmatic people. Single-dose ampuls and single-dose vials of Bupivacaine Hydrochloride
without epinephrine do not contain sodium metabisulfite.
PRECAUTIONS
General: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique,
adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other
resuscitative drugs should be available for immediate use. (See WARNINGS, ADVERSE REACTIONS,
and OVERDOSAGE.) During major regional nerve blocks, the patient should have IV fluids running via
an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic
that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects.
The rapid injection of a large volume of local anesthetic solution should be avoided and fractional
(incremental) doses should be used when feasible.
Epidural Anesthesia: During epidural administration of Bupivacaine Hydrochloride, 0.5% and 0.75%
solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between
doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Injections
should be made slowly, with frequent aspirations before and during the injection to avoid intravascular
injection. Syringe aspirations should also be performed before and during each supplemental injection in
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continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations
for blood are negative.
During the administration of epidural anesthesia, it is recommended that a test dose be administered
initially and the effects monitored before the full dose is given. When using a “continuous” catheter
technique, test doses should be given prior to both the original and all reinforcing doses, because plastic
tubing in the epidural space can migrate into a blood vessel or through the dura. When clinical conditions
permit, the test dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as a
warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine
is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in
heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated
patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15
or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate
increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring
can detect a transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of
Bupivacaine Hydrochloride or an equivalent amount of another local anesthetic to detect an unintended
intrathecal administration. This will be evidenced within a few minutes by signs of spinal block (e.g.,
decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The
Test Dose formulation of Bupivacaine Hydrochloride contains 15 mg of bupivacaine and 15 mcg of
epinephrine in a volume of 3 mL. An intravascular or subarachnoid injection is still possible even if
results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal
or epinephrine-induced cardiovascular effects.
Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with
each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic
degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly
patients and acutely ill patients should be given reduced doses commensurate with their age and physical
status. Local anesthetics should also be used with caution in patients with hypotension or heartblock.
Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs
and the patient’s state of consciousness should be performed after each local anesthetic injection. It should
be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness
and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching,
depression, or drowsiness may be early warning signs of central nervous system toxicity.
Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully
restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood
supply such as digits, nose, external ear, or penis. Patients with hypertensive vascular disease may exhibit
exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.
Because amide-local anesthetics such as Bupivacaine Hydrochloride are metabolized by the liver,
these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients
with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a
greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution
in patients with impaired cardiovascular function because they may be less able to compensate for
functional changes associated with the prolongation of AV conduction produced by these drugs.
Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such
as epinephrine are employed in patients during or following the administration of potent inhalation
anesthetics. In deciding whether to use these products concurrently in the same patient, the combined
action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and
the time since injection, when applicable, should be taken into account.
Many drugs used during the conduct of anesthesia are considered potential triggering agents for
familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may
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trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in
advance, it is suggested that a standard protocol for management should be available. Early unexplained
signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature
elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect
triggering agent(s) and prompt institution of treatment, including oxygen therapy, indicated supportive
measures and dantrolene. (Consult dantrolene sodium intravenous package insert before using.)
Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area,
including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to
systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures
require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and
cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial
injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to
puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local
anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their
circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel
for treating adverse reactions should be immediately available. Dosage recommendations should not be
exceeded. (See DOSAGE AND ADMINISTRATION.)
Use in Ophthalmic Surgery: Clinicians who perform retrobulbar blocks should be aware that there have
been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as with
all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage
respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured (see
also WARNINGS and Use In Head and Neck Area, above). As with other anesthetic procedures, patients
should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which
may occur following relatively low total doses.
A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration
is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local
infiltration, including the conjunctiva (see INDICATIONS AND USAGE and PRECAUTIONS,
General). Mixing Bupivacaine Hydrochloride with other local anesthetics is not recommended because of
insufficient data on the clinical use of such mixtures.
When Bupivacaine Hydrochloride 0.75% is used for retrobulbar block, complete corneal anesthesia
usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of
akinesia rather than anesthesia alone should determine readiness of the patient for surgery.
Information for Patients: When appropriate, patients should be informed in advance that they may
experience temporary loss of sensation and motor activity, usually in the lower half of the body, following
proper administration of caudal or epidural anesthesia. Also, when appropriate, the physician should
discuss other information including adverse reactions in the package insert of Bupivacaine Hydrochloride.
Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing
epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic
antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should
generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is
essential.
Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe,
persistent hypertension or cerebrovascular accidents.
Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate the
carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic potential
and the effect on fertility of bupivacaine hydrochloride have not been determined.
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Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.
Bupivacaine Hydrochloride should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered
subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of
Bupivacaine at term for obstetrical anesthesia or analgesia. (See Labor and Delivery)
Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg
and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to
closure of the hard palate). The high doses are comparable to the daily maximum recommended human
dose (MRHD) of 400 mg/day on a mg/m2 body surface area (BSA) basis. No embryo-fetal effects were
observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal
deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No
Observed Adverse Effect Level representing approximately 1/5th the MRHD on a BSA basis.
In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted
at subcutaneous doses of 4.4, 13.3, & 40 mg/kg, decreased pup survival was observed at the high dose.
The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis.
Labor and Delivery: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75%
BUPIVACAINE HYDROCHLORIDE.
Bupivacaine Hydrochloride is contraindicated for obstetrical paracervical block anesthesia.
Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block
anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See CLINICAL
PHARMACOLOGY, Pharmacokinetics.) The incidence and degree of toxicity depend upon the
procedure performed, the type, and amount of drug used, and the technique of drug administration.
Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system,
peripheral vascular tone, and cardiac function.
Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by
blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help
prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and
electronic fetal monitoring is highly advisable.
Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine
contractility or maternal expulsive efforts. Epidural anesthesia has been reported to prolong the second
stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function.
The use of obstetrical anesthesia may increase the need for forceps assistance.
The use of some local anesthetic drug products during labor and delivery may be followed by
diminished muscle strength and tone for the first day or two of life. This has not been reported with
bupivacaine.
It is extremely important to avoid aortocaval compression by the gravid uterus during administration
of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus
position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to
the left.
Nursing Mothers: Bupivacaine has been reported to be excreted in human milk suggesting that the
nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious
adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue
nursing or not administer bupivacaine, taking into account the importance of the drug to the mother.
Pediatric Use: Until further experience is gained in pediatric patients younger than 12 years,
administration of Bupivacaine Hydrochloride in this age group is not recommended. Continuous infusions
of bupivacaine in children have been reported to result in high systemic levels of bupivacaine and
seizures; high plasma levels may also be associated with cardiovascular abnormalities. (See WARNINGS,
PRECAUTIONS, and OVERDOSAGE.)
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Geriatric Use: Patients over 65 years, particularly those with hypertension, may be at increased risk for
developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride. (See ADVERSE
REACTIONS.)
Elderly patients may require lower doses of Bupivacaine Hydrochloride. (See PRECAUTIONS,
Epidural Anesthesia and DOSAGE AND ADMINISTRATION.)
In clinical studies, differences in various pharmacokinetic parameters have been observed between
elderly and younger patients. (See CLINICAL PHARMACOLOGY.)
This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection, and it may be useful to monitor
renal function. (See CLINICAL PHARMACOLOGY.)
ADVERSE REACTIONS
Reactions to Bupivacaine Hydrochloride are characteristic of those associated with other amide-type local
anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which
may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation.
The most commonly encountered acute adverse experiences which demand immediate counter
measures are related to the central nervous system and the cardiovascular system. These adverse
experiences are generally dose related and due to high plasma levels which may result from overdosage,
rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular
injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional
subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or
nerve blocks near the vertebral column (especially in the head and neck region) may result in
underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and
respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may
occur. This may lead to secondary cardiac arrest if untreated. Patients over 65 years, particularly those
with hypertension, may be at increased risk for experiencing the hypotensive effects of Bupivacaine
Hydrochloride. Factors influencing plasma protein binding, such as acidosis, systemic diseases which
alter protein production, or competition of other drugs for protein binding sites, may diminish individual
tolerance.
Central Nervous System Reactions: These are characterized by excitation and/or depression.
Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to
convulsions. However, excitement may be transient or absent, with depression being the first
manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into
unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting,
chills, and constriction of the pupils.
The incidence of convulsions associated with the use of local anesthetics varies with the procedure
used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity
progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations.
Cardiovascular System Reactions: High doses or unintentional intravascular injection may lead to high
plasma levels and related depression of the myocardium, decreased cardiac output, heartblock,
hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular
fibrillation, and cardiac arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE sections.)
Allergic: Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or
to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in
multiple-dose vials or sulfites in epinephrine-containing solutions. These reactions are characterized by
signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia,
sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly,
anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of
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the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has
not been definitely established.
Neurologic: The incidences of adverse neurologic reactions associated with the use of local anesthetics
may be related to the total dose of local anesthetic administered and are also dependent upon the
particular drug used, the route of administration, and the physical status of the patient. Many of these
effects may be related to local anesthetic techniques, with or without a contribution from the drug.
In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the
subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially
on the amount of drug administered intrathecally and the physiological and physical effects of a dural
puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory
paralysis, and bradycardia.
Neurologic effects following epidural or caudal anesthesia may include spinal block of varying
magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention;
fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia,
paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control all of which may
have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of
labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from
loss of cerebrospinal fluid.
Neurologic effects following other procedures or routes of administration may include persistent
anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery.
OVERDOSAGE
Acute emergencies from local anesthetics are generally related to high plasma levels encountered during
therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution.
(See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.)
Management of Local Anesthetic Emergencies: The first consideration is prevention, best
accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the
patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen
should be administered.
The first step in the management of systemic toxic reactions, as well as underventilation or apnea due
to unintentional subarachnoid injection of drug solution, consists of immediate attention to the
establishment and maintenance of a patent airway and effective assisted or controlled ventilation with
100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask.
This may prevent convulsions if they have not already occurred.
If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of
succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems
and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental
will permit ventilation and counteract central nervous system stimulation, but these drugs also depress
central nervous system, respiratory, and cardiac function, add to postictal depression and may result in
apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered
by those familiar with their use. Immediately after the institution of these ventilatory measures, the
adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may
require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical
situation (such as ephedrine or epinephrine to enhance myocardial contractile force).
Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated
after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent
airway, or if prolonged ventilatory support (assisted or controlled) is indicated.
Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated
rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of
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convulsions. These observations suggest that oxygen consumption and carbon dioxide production are
greatly increased during local anesthetic convulsions and emphasize the importance of immediate and
effective ventilation with oxygen which may avoid cardiac arrest.
If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus
myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias,
bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including
apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local
anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is
not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative
efforts.
The supine position is dangerous in pregnant women at term because of aortocaval compression by
the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension or fetal
bradycardia following regional block, the parturient should be maintained in the left lateral decubitus
position if possible, or manual displacement of the uterus off the great vessels be accomplished.
The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean
arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg
to 8 mg/kg and 38 mg/kg to 54 mg/kg respectively.
DOSAGE AND ADMINISTRATION
The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be
anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of
anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual
tolerance, and the physical condition of the patient. The smallest dose and concentration required to
produce the desired result should be administered. Dosages of Bupivacaine Hydrochloride should be
reduced for elderly and/or debilitated patients and patients with cardiac and/or liver disease. The rapid
injection of a large volume of local anesthetic solution should be avoided and fractional (incremental)
doses should be used when feasible.
For specific techniques and procedures, refer to standard textbooks.
There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of
local anesthetics following arthroscopic and other surgical procedures. Bupivacaine Hydrochloride is not
approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).
In recommended doses, Bupivacaine Hydrochloride produces complete sensory block, but the effect
on motor function differs among the three concentrations.
0.25% — when used for caudal, epidural, or peripheral nerve block, produces incomplete motor
block. Should be used for operations in which muscle relaxation is not important, or when
another means of providing muscle relaxation is used concurrently. Onset of action may be
slower than with the 0.5% or 0.75% solutions.
0.5% — provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be
inadequate for operations in which complete muscle relaxation is essential.
0.75% — produces complete motor block. Most useful for epidural block in abdominal operations
requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical
anesthesia.
The duration of anesthesia with Bupivacaine Hydrochloride is such that for most indications, a single
dose is sufficient.
Maximum dosage limit must be individualized in each case after evaluating the size and physical
status of the patient, as well as the usual rate of systemic absorption from a particular injection site. Most
experience to date is with single doses of Bupivacaine Hydrochloride up to 225 mg with epinephrine
1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on
individualization of each case.
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These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses
have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours.
The duration of anesthetic effect may be prolonged by the addition of epinephrine.
The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in
the average adult. These dosages should be reduced for elderly or debilitated patients. Until further
experience is gained, Bupivacaine Hydrochloride is not recommended for pediatric patients younger than
12 years. Bupivacaine Hydrochloride is contraindicated for obstetrical paracervical blocks, and is not
recommended for intravenous regional anesthesia (Bier Block).
Use in Epidural Anesthesia: During epidural administration of Bupivacaine Hydrochloride, 0.5% and
0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time
between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. In
obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of
the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses
should be preceded by a test dose containing epinephrine if not contraindicated. Use only the single-dose
ampuls and single-dose vials for caudal or epidural anesthesia; the multiple-dose vials contain a
preservative and therefore should not be used for these procedures.
Test Dose for Caudal and Lumbar Epidural Blocks: The Test Dose of Bupivacaine Hydrochloride
(0.5% bupivacaine with 1:200,000 epinephrine in a 3 mL ampul) is recommended for use as a test dose
when clinical conditions permit prior to caudal and lumbar epidural blocks. This may serve as a warning
of unintended intravascular or subarachnoid injection. (See PRECAUTIONS.) The pulse rate and other
signs should be monitored carefully immediately following each test dose administration to detect
possible intravascular injection, and adequate time for onset of spinal block should be allotted to detect
possible intrathecal injection. An intravascular or subarachnoid injection is still possible even if results of
the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or
cardiovascular effects from the epinephrine. (See WARNINGS and OVERDOSAGE.)
Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampuls
and single-dose vials, should be discarded following initial use.
This product should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit. Solutions which are discolored or which contain
particulate matter should not be administered.
wEN-3182v04
Page 12 of 14
Reference ID: 3790419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1.
Recommended Concentrations and Doses of Bupivacaine Hydrochloride
Type of
Block
Conc.
(mL)
Each Dose
(mg)
Motor
Block1
Local infiltration
Epidural
0.25%4
0.75%2,4
0.5%4
up to max.
10-20
10-20
up to max.
75-150
50-100
—
complete
moderate
0.25%4
10-20
25-50
to complete
partial
to moderate
Caudal
0.5%4
15-30
75-150
moderate
0.25%4
15-30
37.5-75
to complete
moderate
Peripheral
0.5%4
5 to
25 to
moderate
nerves
max.
max.
to
0.25%4
5 to max.
12.5 to max.
complete
moderate
to
Retrobulbar3
0.75%4
2-4
15-30
complete
complete
Sympathetic
Epidural3
0.25%
0.5%
20-50
2-3
50-125
10-15
—
—
Test Dose
w/epi
(10-15 micrograms
epinephrine)
1 With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5%
may produce complete motor block. Intercostal nerve block with 0.25% may also produce complete motor block for intra
abdominal surgery.
2
For single-dose use, not for intermittent epidural technique. Not for obstetrical anesthesia.
3
See PRECAUTIONS.
4
Solutions with or without epinephrine.
HOW SUPPLIED
These solutions are not for spinal anesthesia.
Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]
Bupivacaine Hydrochloride — Solutions of Bupivacaine Hydrochloride that do not contain epinephrine
may be autoclaved. Autoclave at 15-pound pressure, 121°C (250°F) for 15 minutes. Do not autoclave
product packaged in AbbojectTM Syringes.
wEN-3182v04
Page 13 of 14
Reference ID: 3790419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Conc.
Size
pH
Package
NDC No.
0.25%
30 mL
4.0 to 6.5
Ampul
0409-1158-01
50 mL
4.0 to 6.5
Ampul
0409-1158-02
0.25%
20 mL
4.0 to 6.5
Sterile Pack Ampul
0409-4272-01
0.25%
10 mL
4.0 to 6.5
Teartop Vial
0409-1159-01
30 mL
4.0 to 6.5
Teartop Vial
0409-1159-02
0.25%
50 mL
4.0 to 6.5
Fliptop Vial (Multiple-dose)
0409-1160-01
0.5%
30 mL
4.0 to 6.5
Ampul
0409-1161-01
0.5%
20 mL
4.0 to 6.5
Sterile Pack Ampul
0409-4273-01
0.5%
50 mL
4.0 to 6.5
Fliptop Vial (Multiple-dose)
0409-1163-01
0.5%
10 mL
4.0 to 6.5
Teartop Vial
0409-1162-01
30 mL
4.0 to 6.5
Teartop Vial
0409-1162-02
0.75%
20 mL
4.0 to 6.5
Sterile Pack Ampul
0409-4274-01
0.75%
10 mL
4.0 to 6.5
Teartop Vial
0409-1165-01
30 mL
4.0 to 6.5
Teartop Vial
0409-1165-02
0.25%
20 mL
4.0 to 6.5
Ampul
0409-5622-01
0.75%
2 mL
4.0 to 6.5
Ampul
0409-5623-02
0.5%
0.5%
20 mL
20 mL
4.0 to 6.5
4.0 to 6.5
Ampul
AbbojectTM Syringe
0409-5757-01
0409-5758-01
Bupivacaine Hydrochloride with epinephrine 1:200,000 (as bitartrate) – Solutions of Bupivacaine
Hydrochloride that contain epinephrine should not be autoclaved and should be protected from light. Do
not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate.
Concentration
Bupivacaine
HCl
Size
pH
Package
NDC No.
0.25%
10 mL
3.3 to 5.5
Teartop Vial
0409-9042-01
0.25%
30 mL
3.3 to 5.5
Teartop Vial
0409-9042-02
0.25%
30 mL
3.3 to 5.5
Teartop Vial
0409-9042-17
0.25%
50 mL
3.3 to 5.5
Fliptop Vial (Multiple-dose)
0409-9043-01
0.5%
10 mL
3.3 to 5.5
Teartop Vial
0409-9045-01
0.5%
30 mL
3.3 to 5.5
Teartop Vial
0409-9045-02
0.5%
30 mL
3.3 to 5.5
Teartop Vial
0409-9045-17
0.5%
50 mL
3.3 to 5.5
Fliptop Vial (Multiple-dose)
0409-9046-01
Revised: 01/2013
AbbojectTM is a registered trademark of the Abbott group of companies.
EN-3182
Hospira, Inc., Lake Forest, IL 60045 USA
wEN-3182v04
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Reference ID: 3790419
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:31.579520
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018053s055lbl.pdf', 'application_number': 18053, 'submission_type': 'SUPPL ', 'submission_number': 55}
|
11,135
|
Rx only
PLATINOL®
(cisplatin for injection, USP)
WARNING
PLATINOL (cisplatin for injection, USP) should be administered under the supervision
of a qualified physician experienced in the use of cancer chemotherapeutic agents.
Appropriate management of therapy and complications is possible only when adequate
diagnostic and treatment facilities are readily available.
Cumulative renal toxicity associated with PLATINOL is severe. Other major dose-related
toxicities are myelosuppression, nausea, and vomiting.
Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus,
and/or loss of high frequency hearing and occasionally deafness, is significant.
Anaphylactic-like reactions to PLATINOL have been reported. Facial edema,
bronchoconstriction, tachycardia, and hypotension may occur within minutes of
PLATINOL administration. Epinephrine, corticosteroids, and antihistamines have been
effectively employed to alleviate symptoms (see WARNINGS and ADVERSE
REACTIONS).
Exercise caution to prevent inadvertent PLATINOL overdose. Doses greater than
100 mg/m2/cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid
inadvertent PLATINOL overdose due to confusion with PARAPLATIN® (carboplatin)
or prescribing practices that fail to differentiate daily doses from total dose per cycle.
DESCRIPTION
PLATINOL® (cisplatin for injection, USP) is a white to light yellow lyophilized powder.
Each vial of PLATINOL contains 50 mg cisplatin, 450 mg Sodium Chloride, USP, and
500 mg Mannitol, USP.
1
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The active ingredient, cisplatin, is a yellow to orange crystalline powder with the
molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy
metal complex containing a central atom of platinum surrounded by two chloride atoms
and two ammonia molecules in the cis position. It is soluble in water or saline at
1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207° C. structural formula
CLINICAL PHARMACOLOGY
Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with
a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2
doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen
following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total body
clearances and volumes of distribution at steady-state for cisplatin are about 15 to
16 L/h/m2 and 11 to 12 L/m2.
Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to
chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups,
than to enzyme-catalyzed metabolism. At physiological pH in the presence of 0.1M
NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis
diammine platinum (II) in nearly equal concentrations. The latter, combined with the
possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or
proteins, accounts for the instability of cisplatin in biological matrices. The ratios of
cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between
patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.
Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins
that is characteristic of normal drug-protein binding. However, the platinum from
cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including
albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two
hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound.
The complexes between albumin and the platinum from cisplatin do not dissociate to a
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
significant extent and are slowly eliminated with a minimum half-life of five days or
more.
Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest
in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and
spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is
present in tissues for as long as 180 days after the last administration. With the exception
of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower
than the concentrations in the organ where the tumor is located. Different metastatic sites
in the same patient may have different platinum concentrations. Hepatic metastases have
the highest platinum concentrations, but these are similar to the platinum concentrations
in normal liver. Maximum red blood cell concentrations of platinum are reached within
90 to 150 minutes after a 100 mg/m2 dose of cisplatin and decline in a biphasic manner
with a terminal half-life of 36 to 47 days.
Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions
varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered
platinum is excreted in the urine in 24 hours. Over five days following administration of
40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of
35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary
recoveries of platinum of about 14% to 30% of the dose are found following five daily
administrations of 20, 30, or 40 mg/m2/day. Only a small percentage of the administered
platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in
the urine in 24 hours is excreted within the first few hours. Platinum-containing species
excreted in the urine are the same as those found following the incubation of cisplatin
with urine from healthy subjects, except that the proportions are different.
The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of
the dose excreted within one hour after administration of 50 mg/m2. The mean renal
clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following
administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively.
The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular
filtration rate indicating that cisplatin or other platinum-containing molecules are actively
secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable
3
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For current labeling information, please visit https://www.fda.gov/drugsatfda
and is dependent on dose, urine flow rate, and individual variability in the extent of active
secretion and possible tubular reabsorption.
There is a potential for accumulation of ultrafilterable platinum plasma concentrations
whenever cisplatin is administered on a daily basis but not when dosed on an intermittent
basis.
No significant relationships exist between the renal clearance of either free platinum or
cisplatin and creatinine clearance.
Although small amounts of platinum are present in the bile and large intestine after
administration of cisplatin, the fecal excretion of platinum appears to be insignificant.
INDICATIONS AND USAGE
PLATINOL (cisplatin for injection, USP) is indicated as therapy to be employed as
follows:
Metastatic Testicular Tumors
In established combination therapy with other approved chemotherapeutic agents in
patients with metastatic testicular tumors who have already received appropriate surgical
and/or radiotherapeutic procedures.
Metastatic Ovarian Tumors
In established combination therapy with other approved chemotherapeutic agents in
patients with metastatic ovarian tumors who have already received appropriate surgical
and/or radiotherapeutic procedures. An established combination consists of PLATINOL
and cyclophosphamide. PLATINOL, as a single agent, is indicated as secondary therapy
in patients with metastatic ovarian tumors refractory to standard chemotherapy who have
not previously received PLATINOL therapy.
Advanced Bladder Cancer
PLATINOL is indicated as a single agent for patients with transitional cell bladder cancer
which is no longer amenable to local treatments, such as surgery and/or radiotherapy.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
PLATINOL is contraindicated in patients with preexisting renal impairment. PLATINOL
should not be employed in myelosuppressed patients, or in patients with hearing
impairment.
PLATINOL is contraindicated in patients with a history of allergic reactions to
PLATINOL or other platinum-containing compounds.
WARNINGS
PLATINOL produces cumulative nephrotoxicity which is potentiated by aminoglycoside
antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and
magnesium, sodium, potassium, and calcium levels should be measured prior to initiating
therapy, and prior to each subsequent course. At the recommended dosage, PLATINOL
should not be given more frequently than once every 3 to 4 weeks (see ADVERSE
REACTIONS). Elderly patients may be more susceptible to nephrotoxicity (see
PRECAUTIONS: Geriatric Use).
There are reports of severe neuropathies in patients in whom regimens are employed
using higher doses of PLATINOL or greater dose frequencies than those recommended.
These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove
distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients
may be more susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric
Use).
Loss of motor function has also been reported.
Anaphylactic-like reactions to PLATINOL have been reported. These reactions have
occurred within minutes of administration to patients with prior exposure to PLATINOL,
and have been alleviated by administration of epinephrine, corticosteroids, and
antihistamines.
Since ototoxicity of PLATINOL is cumulative, audiometric testing should be performed
prior to initiating therapy and prior to each subsequent dose of drug (see ADVERSE
REACTIONS).
PLATINOL can cause fetal harm when administered to a pregnant woman. PLATINOL
is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
culture. In mice PLATINOL is teratogenic and embryotoxic. If this drug is used during
pregnancy or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to the fetus. Patients should be advised to avoid
becoming pregnant.
The carcinogenic effect of PLATINOL was studied in BD IX rats. PLATINOL was
administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body
weight per week. Four hundred and fifty-five days after the first application, 33 animals
died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma.
The development of acute leukemia coincident with the use of PLATINOL has been
reported. In these reports, PLATINOL was generally given in combination with other
leukemogenic agents.
PRECAUTIONS
Peripheral blood counts should be monitored weekly. Liver function should be monitored
periodically. Neurologic examination should also be performed regularly (see
ADVERSE REACTIONS).
Drug Interactions
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin
therapy.
In a randomized trial in advanced ovarian cancer, response duration was adversely
affected
when
pyridoxine
was
used
in
combination
with
altretamine
(hexamethylmelamine) and PLATINOL.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See WARNINGS.
Pregnancy
Category D. See WARNINGS.
Nursing Mothers
Cisplatin has been reported to be found in human milk; patients receiving PLATINOL
should not breast-feed.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Insufficient data are available from clinical trials of cisplatin in the treatment of
metastatic testicular tumors or advanced bladder cancer to determine whether elderly
patients respond differently than younger patients. In four clinical trials of combination
chemotherapy for advanced ovarian carcinoma, 1484 patients received cisplatin either in
combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than
65 years. In these trials, age was not found to be a prognostic factor for survival.
However, in a later secondary analysis for one of these trials, elderly patients were found
to have shorter survival compared with younger patients. In all four trials, elderly patients
experienced more severe neutropenia than younger patients. Higher incidences of severe
thrombocytopenia and leukopenia were also seen in elderly compared with younger
patients, although not in all cisplatin-containing treatment arms. In the two trials where
nonhematologic toxicity was evaluated according to age, elderly patients had a
numerically higher incidence of peripheral neuropathy than younger patients. Other
reported clinical experience suggests that elderly patients may be more susceptible to
myelosuppression, infectious complications, and nephrotoxicity than younger patients.
Cisplatin is known to be substantially excreted by the kidney and is contraindicated in
patients with preexisting renal impairment. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection, and renal function
should be monitored.
ADVERSE REACTIONS
Nephrotoxicity
Dose-related and cumulative renal insufficiency, including acute renal failure, is the
major dose-limiting toxicity of PLATINOL. Renal toxicity has been noted in 28% to 36%
of patients treated with a single dose of 50 mg/m2. It is first noted during the second week
after a dose and is manifested by elevations in BUN and creatinine, serum uric acid
and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and
severe with repeated courses of the drug. Renal function must return to normal
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
before another dose of PLATINOL can be given. Elderly patients may be more
susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).
Impairment of renal function has been associated with renal tubular damage. The
administration of PLATINOL using a 6- to 8-hour infusion with intravenous hydration,
and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can
occur after utilization of these procedures.
Ototoxicity
Ototoxicity has been observed in up to 31% of patients treated with a single dose of
PLATINOL 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high
frequency range (4000 to 8000 Hz). Decreased ability to hear normal conversational
tones may occur. Deafness after the initial dose of PLATINOL (cisplatin for injection,
USP) has been reported. Ototoxic effects may be more severe in children receiving
PLATINOL. Hearing loss can be unilateral or bilateral and tends to become more
frequent and severe with repeated doses. Ototoxicity may be enhanced with prior or
simultaneous cranial irradiation. It is unclear whether PLATINOL-induced ototoxicity is
reversible. Ototoxic effects may be related to the peak plasma concentration of
PLATINOL. Careful monitoring of audiometry should be performed prior to initiation of
therapy and prior to subsequent doses of PLATINOL.
Vestibular toxicity has also been reported.
Ototoxicity may become more severe in patients being treated with other drugs with
nephrotoxic potential.
Hematologic
Myelosuppression occurs in 25% to 30% of patients treated with PLATINOL. The nadirs
in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with
most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia
are more pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g
hemoglobin/100 mL) occurs at approximately the same frequency and with the same
timing as leukopenia and thrombocytopenia. Fever and infection have also been reported
in patients with neutropenia. Potential fatalities due to infection (secondary to
myelosuppression) have been reported. Elderly patients may be more susceptible to
myelosuppression (see PRECAUTIONS: Geriatric Use).
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In addition to anemia secondary to myelosuppression, a Coombs’ positive hemolytic
anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course
of treatment may be accompanied by increased hemolysis and this risk should be
weighed by the treating physician.
The development of acute leukemia coincident with the use of PLATINOL has been
reported. In these reports, PLATINOL was generally given in combination with other
leukemogenic agents.
Gastrointestinal
Marked nausea and vomiting occur in almost all patients treated with PLATINOL, and
may be so severe that the drug must be discontinued. Nausea and vomiting may begin
within 1 to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting,
nausea and/or anorexia may persist for up to 1 week after treatment.
Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy)
has occurred in patients attaining complete emetic control on the day of PLATINOL
therapy.
Diarrhea has also been reported.
OTHER TOXICITIES
Vascular toxicities coincident with the use of PLATINOL in combination with other
antineoplastic agents have been reported. The events are clinically heterogeneous and
may
include
myocardial
infarction,
cerebrovascular
accident,
thrombotic
microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various
mechanisms have been proposed for these vascular complications. There are also reports
of Raynaud’s phenomenon occurring in patients treated with the combination of
bleomycin, vinblastine with or without PLATINOL. It has been suggested that
hypomagnesemia developing coincident with the use of PLATINOL may be an added,
although not essential, factor associated with this event. However, it is currently
unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying
vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any
of these factors.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Serum Electrolyte Disturbances
Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia
have been reported to occur in patients treated with PLATINOL and are probably related
to renal tubular damage. Tetany has been reported in those patients with hypocalcemia
and hypomagnesemia. Generally, normal serum electrolyte levels are restored by
administering supplemental electrolytes and discontinuing PLATINOL.
Inappropriate antidiuretic hormone syndrome has also been reported.
Hyperuricemia
Hyperuricemia has been reported to occur at approximately the same frequency as the
increases in BUN and serum creatinine.
It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid
generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia
effectively reduces uric acid levels.
Neurotoxicity
See WARNINGS.
Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The
neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic
symptoms have been reported to occur after a single dose. Although symptoms and signs
of PLATINOL neuropathy usually develop during treatment, symptoms of neuropathy
may begin 3 to 8 weeks after the last dose of PLATINOL. PLATINOL therapy should be
discontinued when the symptoms are first observed. The neuropathy, however, may
progress further even after stopping treatment. Preliminary evidence suggests peripheral
neuropathy may be irreversible in some patients. Elderly patients may be more
susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric Use).
Lhermitte’s sign, dorsal column myelopathy, and autonomic neuropathy have also been
reported.
Loss of taste and seizures have also been reported.
Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of
sudden onset and short duration, have been reported and were usually associated in
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients receiving a relatively high cumulative dose of PLATINOL and with a relatively
advanced symptomatic stage of peripheral neuropathy.
Ocular Toxicity
Optic neuritis, papilledema, and cerebral blindness have been reported in patients
receiving standard recommended doses of PLATINOL. Improvement and/or total
recovery usually occurs after discontinuing PLATINOL. Steroids with or without
mannitol have been used; however, efficacy has not been established.
Blurred vision and altered color perception have been reported after the use of regimens
with higher doses of PLATINOL or greater dose frequencies than recommended in the
package insert. The altered color perception manifests as a loss of color discrimination,
particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular
retinal pigmentation of the macular area.
Anaphylactic-Like Reactions
Anaphylactic-like reactions have been reported in patients previously exposed to
PLATINOL. The reactions consist of facial edema, wheezing, tachycardia, and
hypotension within a few minutes of drug administration. Reactions may be controlled by
intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients
receiving PLATINOL should be observed carefully for possible anaphylactic-like
reactions and supportive equipment and medication should be available to treat such a
complication.
Hepatotoxicity
Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been
reported to be associated with PLATINOL administration at the recommended doses.
Other Events
Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia,
and dehydration have been reported.
Local soft tissue toxicity has been reported following extravasation of PLATINOL.
Severity of the local tissue toxicity appears to be related to the concentration of the
PLATINOL solution. Infusion of solutions with a PLATINOL concentration greater than
0.5 mg/mL may result in tissue cellulitis, fibrosis, and necrosis.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Caution should be exercised to prevent inadvertent overdosage with PLATINOL.
Acute overdosage with this drug may result in kidney failure, liver failure, deafness,
ocular toxicity (including detachment of the retina), significant myelosuppression,
intractable nausea and vomiting and/or neuritis. In addition, death can occur following
overdosage.
No proven antidotes have been established for PLATINOL overdosage. Hemodialysis,
even when initiated four hours after the overdosage, appears to have little effect on
removing platinum from the body because of PLATINOL’s rapid and high degree of
protein binding. Management of overdosage should include general supportive measures
to sustain the patient through any period of toxicity that may occur.
DOSAGE AND ADMINISTRATION
Note: Needles or intravenous sets containing aluminum parts that may come in
contact with PLATINOL should not be used for preparation or administration.
Aluminum reacts with PLATINOL, causing precipitate formation and a loss of
potency.
Metastatic Testicular Tumors
The usual PLATINOL dose for the treatment of testicular cancer in combination with
other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.
Metastatic Ovarian Tumors
The usual PLATINOL dose for the treatment of metastatic ovarian tumors in combination
with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every 4 weeks (DAY 1).
The dose of cyclophosphamide when used in combination with PLATINOL is
600 mg/m2 IV once every 4 weeks (DAY 1).
For directions for the administration of cyclophosphamide, refer to the cyclophosphamide
package insert.
In combination therapy, PLATINOL and cyclophosphamide are administered
sequentially.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
As a single agent, PLATINOL should be administered at a dose of 100 mg/m2 IV per
cycle once every 4 weeks.
Advanced Bladder Cancer
PLATINOL should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per
cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation
therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of
50 mg/m2 per cycle repeated every 4 weeks is recommended.
All Patients
Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a
PLATINOL dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in
1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour
period. If diluted solution is not to be used within 6 hours, protect solution from light.
Adequate hydration and urinary output must be maintained during the following 24
hours.
A repeat course of PLATINOL should not be given until the serum creatinine is below
1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be
given until circulating blood elements are at an acceptable level (platelets ≥100,000/mm3,
WBC ≥4000/mm3). Subsequent doses of PLATINOL should not be given until an
audiometric analysis indicates that auditory acuity is within normal limits.
PREPARATION OF INTRAVENOUS SOLUTIONS
Preparation Precautions
Caution should be exercised in handling the powder and preparing the solution of
cisplatin. Procedures for proper handling and disposal of anticancer drugs should be
utilized. Several guidelines on this subject have been published.1-4 To minimize the risk
of dermal exposure, always wear impervious gloves when handling vials and IV sets
containing PLATINOL for injection.
Skin reactions associated with accidental exposure to cisplatin may occur. The use of
gloves is recommended. If PLATINOL powder or PLATINOL solution contacts the skin
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
or mucosa, immediately and thoroughly wash the skin with soap and water and flush the
mucosa with water. More information is available in the references listed below.
Instructions for Preparation
The 50 mg vials should be reconstituted with 50 mL of Sterile Water for Injection, USP.
Each mL of the resulting solution will contain 1 mg of PLATINOL.
Reconstitution as recommended results in a clear, colorless to slight yellow solution.
The reconstituted solution should be used intravenously only and should be administered
by IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
NOTE TO PHARMACIST: Exercise caution to prevent inadvertent PLATINOL
overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum
and flip-off seal of vial have been imprinted with the following statement:
CALL DR. IF DOSE>100 MG/M2/CYCLE.
STABILITY
Unopened vials of dry powder are stable for the lot life indicated on the package when
stored at room temperature (25° C, 77° F).
The reconstituted solution is stable for 20 hours at room temperature (25° C, 77° F).
Solution removed from the amber vial should be protected from light if it is not to be
used within six hours.
Important Note: Once reconstituted, the solution should be kept at room temperature
(25° C, 77° F). If the reconstituted solution is refrigerated a precipitate will form.
HOW SUPPLIED
PLATINOL® (cisplatin for injection, USP)
NDC 0015-3072-20—Each amber vial contains 50 mg of cisplatin
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
REFERENCES
1.
NIOSH Alert: Preventing occupational exposures to antineoplastic and other
hazardous drugs in healthcare settings. 2004. U.S. Department of Health and
Human Services, Public Health Service, Centers for Disease Control and
Prevention, National Institute for Occupational Safety and Health, DHHS
(NIOSH) Publication No. 2004-165.
2.
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling
occupational
exposure
to
hazardous
drugs.
OSHA,
1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.
3.
American Society of Health-System Pharmacists. ASHP guidelines on handling
hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4.
Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy
guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology
Nursing Society.
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
Made in Italy
Rev July 2010
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rx only
PLATINOL®-AQ
(cisplatin injection)
WARNING
PLATINOL-AQ (cisplatin injection) should be administered under the supervision of a
qualified physician experienced in the use of cancer chemotherapeutic agents.
Appropriate management of therapy and complications is possible only when adequate
diagnostic and treatment facilities are readily available.
Cumulative renal toxicity associated with PLATINOL-AQ is severe. Other major dose-
related toxicities are myelosuppression, nausea, and vomiting.
Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus,
and/or loss of high frequency hearing and occasionally deafness, is significant.
Anaphylactic-like reactions to PLATINOL-AQ have been reported. Facial edema,
bronchoconstriction, tachycardia, and hypotension may occur within minutes of
PLATINOL-AQ administration. Epinephrine, corticosteroids, and antihistamines have
been effectively employed to alleviate symptoms (see WARNINGS and ADVERSE
REACTIONS sections).
Exercise caution to prevent inadvertent PLATINOL-AQ overdose. Doses greater
than 100 mg/m2/cycle once every 3 to 4 weeks are rarely used. Care must be taken to
avoid inadvertent PLATINOL-AQ overdose due to confusion with PARAPLATIN®
(carboplatin) or prescribing practices that fail to differentiate daily doses from total dose
per cycle.
DESCRIPTION
PLATINOL®-AQ (cisplatin injection) infusion concentrate is a clear, colorless, sterile
aqueous solution available in amber vials. Each 50 mL or 100 mL amber vial of infusion
concentrate contains: 1 mg/mL cisplatin, 9 mg/mL sodium chloride, hydrochloric acid
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
and sodium hydroxide to approximate pH of 4.0, and water for injection to a final volume
of 50 mL or 100 mL, respectively.
PLATINOL®-AQ (cisplatin injection) infusion concentrate must be further diluted prior
to administration (see DOSAGE AND ADMINISTRATION: All Patients).
The active ingredient, cisplatin, is a yellow to orange crystalline powder with the
molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy
metal complex containing a central atom of platinum surrounded by two chloride atoms
and two ammonia molecules in the cis position. It is soluble in water or saline at
1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207° C. structural formula
CLINICAL PHARMACOLOGY
Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with
a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2
doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen
following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total-body
clearances and volumes of distribution at steady-state for cisplatin are about 15 to
16 L/h/m2 and 11 to 12 L/m2.
Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to
chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups,
than to enzyme-catalyzed metabolism. At physiological pH in the presence of 0.1M
NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis
diammine platinum (II) in nearly equal concentrations. The latter, combined with the
possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or
proteins, accounts for the instability of cisplatin in biological matrices. The ratios of
cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between
patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins
that is characteristic of normal drug-protein binding. However, the platinum from
cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including
albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two
hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound.
The complexes between albumin and the platinum from cisplatin do not dissociate to a
significant extent and are slowly eliminated with a minimum half-life of five days or
more.
Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest
in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and
spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is
present in tissues for as long as 180 days after the last administration. With the exception
of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower
than the concentrations in the organ where the tumor is located. Different metastatic sites
in the same patient may have different platinum concentrations. Hepatic metastases have
the highest platinum concentrations, but these are similar to the platinum concentrations
in normal liver. Maximum red blood cell concentrations of platinum are reached within
90 to 150 minutes after a 100 mg/m2 dose of cisplatin and decline in a biphasic manner
with a terminal half-life of 36 to 47 days.
Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions
varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered
platinum is excreted in the urine in 24 hours. Over five days following administration of
40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of
35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary
recoveries of platinum of about 14% to 30% of the dose are found following five daily
administrations of 20, 30, or 40 mg/m2/day. Only a small percentage of the administered
platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in
the urine in 24 hours is excreted within the first few hours. Platinum-containing species
excreted in the urine are the same as those found following the incubation of cisplatin
with urine from healthy subjects, except that the proportions are different.
The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of
the dose excreted within one hour after administration of 50 mg/m2. The mean renal
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following
administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively.
The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular
filtration rate indicating that cisplatin or other platinum-containing molecules are actively
secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable
and is dependent on dose, urine flow rate, and individual variability in the extent of active
secretion and possible tubular reabsorption.
There is a potential for accumulation of ultrafilterable platinum plasma concentrations
whenever cisplatin is administered on a daily basis but not when dosed on an intermittent
basis.
No significant relationships exist between the renal clearance of either free platinum or
cisplatin and creatinine clearance.
Although small amounts of platinum are present in the bile and large intestine after
administration of cisplatin, the fecal excretion of platinum appears to be insignificant.
INDICATIONS
PLATINOL-AQ (cisplatin injection) is indicated as therapy to be employed as follows:
Metastatic Testicular Tumors
In established combination therapy with other approved chemotherapeutic agents in
patients with metastatic testicular tumors who have already received appropriate surgical
and/or radiotherapeutic procedures.
Metastatic Ovarian Tumors
In established combination therapy with other approved chemotherapeutic agents in
patients with metastatic ovarian tumors who have already received appropriate surgical
and/or
radiotherapeutic
procedures.
An
established
combination
consists
of
PLATINOL-AQ and cyclophosphamide. PLATINOL-AQ, as a single agent, is indicated
as secondary therapy in patients with metastatic ovarian tumors refractory to standard
chemotherapy who have not previously received PLATINOL-AQ therapy.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Advanced Bladder Cancer
PLATINOL-AQ is indicated as a single agent for patients with transitional cell bladder
cancer which is no longer amenable to local treatments, such as surgery and/or
radiotherapy.
CONTRAINDICATIONS
PLATINOL-AQ is contraindicated in patients with preexisting renal impairment.
PLATINOL-AQ should not be employed in myelosuppressed patients, or in patients with
hearing impairment.
PLATINOL-AQ is contraindicated in patients with a history of allergic reactions to
PLATINOL-AQ or other platinum-containing compounds.
WARNINGS
PLATINOL-AQ produces cumulative nephrotoxicity which is potentiated by
aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine
clearance, and magnesium, sodium, potassium, and calcium levels should be measured
prior to initiating therapy, and prior to each subsequent course. At the recommended
dosage, PLATINOL-AQ should not be given more frequently than once every 3 to 4
weeks (see ADVERSE REACTIONS). Elderly patients may be more susceptible to
nephrotoxicity (see PRECAUTIONS: Geriatric Use).
There are reports of severe neuropathies in patients in whom regimens are employed
using higher doses of PLATINOL-AQ or greater dose frequencies than those
recommended. These neuropathies may be irreversible and are seen as paresthesias in a
stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation.
Elderly
patients
may
be
more
susceptible
to
peripheral
neuropathy
(see
PRECAUTIONS: Geriatric Use).
Loss of motor function has also been reported.
Anaphylactic-like reactions to PLATINOL-AQ have been reported. These reactions have
occurred within minutes of administration to patients with prior exposure to
PLATINOL-AQ, and have been alleviated by administration of epinephrine,
corticosteroids, and antihistamines.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Since ototoxicity of PLATINOL-AQ is cumulative, audiometric testing should be
performed prior to initiating therapy and prior to each subsequent dose of drug (see
ADVERSE REACTIONS).
PLATINOL-AQ can cause fetal harm when administered to a pregnant woman.
PLATINOL-AQ is mutagenic in bacteria and produces chromosome aberrations in
animal cells in tissue culture. In mice PLATINOL-AQ is teratogenic and embryotoxic. If
this drug is used during pregnancy or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to the fetus. Patients should be
advised to avoid becoming pregnant.
The carcinogenic effect of PLATINOL-AQ was studied in BD IX rats. PLATINOL-AQ
was administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body
weight per week. Four hundred and fifty-five days after the first application, 33 animals
died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma.
The development of acute leukemia coincident with the use of PLATINOL-AQ has been
reported. In these reports, PLATINOL-AQ was generally given in combination with
other leukemogenic agents.
PRECAUTIONS
Peripheral blood counts should be monitored weekly. Liver function should be monitored
periodically. Neurologic examination should also be performed regularly (see
ADVERSE REACTIONS).
Drug Interactions
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin
therapy.
In a randomized trial in advanced ovarian cancer, response duration was adversely
affected
when
pyridoxine
was
used
in
combination
with
altretamine
(hexamethylmelamine) and PLATINOL-AQ.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See WARNINGS.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy
Pregnancy Category D
See WARNINGS.
Nursing Mothers
Cisplatin has been reported to be found in human milk; patients receiving
PLATINOL-AQ should not breast-feed.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Insufficient data are available from clinical trials of cisplatin in the treatment of
metastatic testicular tumors or advanced bladder cancer to determine whether elderly
patients respond differently than younger patients. In four clinical trials of combination
chemotherapy for advanced ovarian carcinoma, 1484 patients received cisplatin either in
combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than
65 years. In these trials, age was not found to be a prognostic factor for survival.
However, in a later secondary analysis for one of these trials, elderly patients were found
to have shorter survival compared with younger patients. In all four trials, elderly patients
experienced more severe neutropenia than younger patients. Higher incidences of severe
thrombocytopenia and leukopenia were also seen in elderly compared with younger
patients, although not in all cisplatin-containing treatment arms. In the two trials where
nonhematologic toxicity was evaluated according to age, elderly patients had a
numerically higher incidence of peripheral neuropathy than younger patients. Other
reported clinical experience suggests that elderly patients may be more susceptible to
myelosuppression, infectious complications, and nephrotoxicity than younger patients.
Cisplatin is known to be substantially excreted by the kidney and is contraindicated in
patients with preexisting renal impairment. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection, and renal function
should be monitored.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Nephrotoxicity
Dose-related and cumulative renal insufficiency, including acute renal failure, is the
major dose-limiting toxicity of PLATINOL-AQ. Renal toxicity has been noted in 28% to
36% of patients treated with a single dose of 50 mg/m2. It is first noted during the second
week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid
and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and
severe with repeated courses of the drug. Renal function must return to normal
before another dose of PLATINOL-AQ can be given. Elderly patients may be more
susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).
Impairment of renal function has been associated with renal tubular damage. The
administration of PLATINOL-AQ using a 6- to 8-hour infusion with intravenous
hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity
still can occur after utilization of these procedures.
Ototoxicity
Ototoxicity has been observed in up to 31% of patients treated with a single dose of
PLATINOL-AQ 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high
frequency range (4000 to 8000 Hz). Decreased ability to hear normal conversational
tones may occur. Deafness after the initial dose of PLATINOL-AQ has been reported.
Ototoxic effects may be more severe in children receiving PLATINOL-AQ. Hearing loss
can be unilateral or bilateral and tends to become more frequent and severe with repeated
doses. Ototoxicity may be enhanced with prior or simultaneous cranial irradiation. It is
unclear whether PLATINOL-AQ–induced ototoxicity is reversible. Ototoxic effects may
be related to the peak plasma concentration of PLATINOL-AQ. Careful monitoring of
audiometry should be performed prior to initiation of therapy and prior to subsequent
doses of PLATINOL-AQ.
Vestibular toxicity has also been reported.
Ototoxicity may become more severe in patients being treated with other drugs with
nephrotoxic potential.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hematologic
Myelosuppression occurs in 25% to 30% of patients treated with PLATINOL-AQ. The
nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to
45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and
thrombocytopenia are more pronounced at higher doses (>50 mg/m2). Anemia (decrease
of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the
same timing as leukopenia and thrombocytopenia. Fever and infection have also been
reported in patients with neutropenia. Potential fatalities due to infection (secondary to
myelosuppression) have been reported. Elderly patients may be more susceptible to
myelosuppression (see PRECAUTIONS: Geriatric Use).
In addition to anemia secondary to myelosuppression, a Coombs’ positive hemolytic
anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course
of treatment may be accompanied by increased hemolysis and this risk should be
weighed by the treating physician.
The development of acute leukemia coincident with the use of PLATINOL-AQ has been
reported. In these reports, PLATINOL-AQ was generally given in combination with
other leukemogenic agents.
Gastrointestinal
Marked nausea and vomiting occur in almost all patients treated with PLATINOL-AQ,
and may be so severe that the drug must be discontinued. Nausea and vomiting may
begin within 1 to 4 hours after treatment and last up to 24 hours. Various degrees of
vomiting, nausea and/or anorexia may persist for up to 1 week after treatment.
Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy)
has occurred in patients attaining complete emetic control on the day of PLATINOL-AQ
therapy.
Diarrhea has also been reported.
OTHER TOXICITIES
Vascular toxicities coincident with the use of PLATINOL-AQ in combination with other
antineoplastic agents have been reported. The events are clinically heterogeneous and
may
include
myocardial
infarction,
cerebrovascular
accident,
thrombotic
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various
mechanisms have been proposed for these vascular complications. There are also reports
of Raynaud’s phenomenon occurring in patients treated with the combination of
bleomycin, vinblastine with or without PLATINOL-AQ. It has been suggested that
hypomagnesemia developing coincident with the use of PLATINOL-AQ may be an
added, although not essential, factor associated with this event. However, it is currently
unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying
vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any
of these factors.
Serum Electrolyte Disturbances
Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia
have been reported to occur in patients treated with PLATINOL-AQ and are probably
related to renal tubular damage. Tetany has been reported in those patients with
hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are
restored by administering supplemental electrolytes and discontinuing PLATINOL-AQ.
Inappropriate antidiuretic hormone syndrome has also been reported.
Hyperuricemia
Hyperuricemia has been reported to occur at approximately the same frequency as the
increases in BUN and serum creatinine.
It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid
generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia
effectively reduces uric acid levels.
Neurotoxicity
See WARNINGS.
Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The
neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic
symptoms have been reported to occur after a single dose. Although symptoms and signs
of PLATINOL-AQ neuropathy usually develop during treatment, symptoms of
neuropathy may begin 3 to 8 weeks after the last dose of PLATINOL-AQ.
PLATINOL-AQ therapy should be discontinued when the symptoms are first observed.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The neuropathy, however, may progress further even after stopping treatment.
Preliminary evidence suggests peripheral neuropathy may be irreversible in some
patients. Elderly patients may be more susceptible to peripheral neuropathy (see
PRECAUTIONS: Geriatric Use).
Lhermitte’s sign, dorsal column myelopathy, and autonomic neuropathy have also been
reported.
Loss of taste and seizures have also been reported.
Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of
sudden onset and short duration, have been reported and were usually associated in
patients receiving a relatively high cumulative dose of PLATINOL-AQ and with a
relatively advanced symptomatic stage of peripheral neuropathy.
Ocular Toxicity
Optic neuritis, papilledema, and cerebral blindness have been reported in patients
receiving standard recommended doses of PLATINOL-AQ. Improvement and/or total
recovery usually occurs after discontinuing PLATINOL-AQ. Steroids with or without
mannitol have been used; however, efficacy has not been established.
Blurred vision and altered color perception have been reported after the use of regimens
with higher doses of PLATINOL-AQ or greater dose frequencies than recommended in
the package insert. The altered color perception manifests as a loss of color
discrimination, particularly in the blue-yellow axis. The only finding on funduscopic
exam is irregular retinal pigmentation of the macular area.
Anaphylactic-Like Reactions
Anaphylactic-like reactions have been reported in patients previously exposed to
PLATINOL-AQ. The reactions consist of facial edema, wheezing, tachycardia, and
hypotension within a few minutes of drug administration. Reactions may be controlled by
intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients
receiving PLATINOL-AQ should be observed carefully for possible anaphylactic-like
reactions and supportive equipment and medication should be available to treat such a
complication.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hepatotoxicity
Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been
reported to be associated with PLATINOL-AQ administration at the recommended doses.
Other Events
Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia,
and dehydration have been reported.
Local soft tissue toxicity has been reported following extravasation of PLATINOL-AQ.
Severity of the local tissue toxicity appears to be related to the concentration of the
PLATINOL-AQ solution. Infusion of solutions with a PLATINOL-AQ concentration
greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, and necrosis.
OVERDOSAGE
Caution
should
be
exercised
to
prevent
inadvertent
overdosage
with
PLATINOL-AQ. Acute overdosage with this drug may result in kidney failure, liver
failure, deafness, ocular toxicity (including detachment of the retina), significant
myelosuppression, intractable nausea and vomiting and/or neuritis. In addition, death can
occur following overdosage.
No proven antidotes have been established for PLATINOL-AQ overdosage.
Hemodialysis, even when initiated four hours after the overdosage, appears to have little
effect on removing platinum from the body because of PLATINOL-AQ’s rapid and high
degree of protein binding. Management of overdosage should include general supportive
measures to sustain the patient through any period of toxicity that may occur.
DOSAGE AND ADMINISTRATION
Note: Needles or intravenous sets containing aluminum parts that may come in
contact with PLATINOL-AQ should not be used for preparation or administration.
Aluminum reacts with PLATINOL-AQ, causing precipitate formation and a loss of
potency.
Metastatic Testicular Tumors
The usual PLATINOL-AQ dose for the treatment of testicular cancer in combination with
other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Metastatic Ovarian Tumors
The usual PLATINOL-AQ dose for the treatment of metastatic ovarian tumors in
combination with cyclophosphamide is 75–100 mg/m2 IV per cycle once every four
weeks (DAY 1).
The dose of cyclophosphamide when used in combination with PLATINOL-AQ is
600 mg/m2 IV once every 4 weeks (DAY 1).
For directions for the administration of cyclophosphamide, refer to the cyclophosphamide
package insert.
In combination therapy, PLATINOL-AQ and cyclophosphamide are administered
sequentially.
As a single agent, PLATINOL-AQ should be administered at a dose of 100 mg/m2 IV per
cycle once every four weeks.
Advanced Bladder Cancer
PLATINOL-AQ should be administered as a single agent at a dose of 50 to 70 mg/m2 IV
per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation
therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of
50 mg/m2 per cycle repeated every 4 weeks is recommended.
All Patients
Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a
PLATINOL-AQ dose is recommended. The drug is then diluted in 2 liters of 5%
Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6
to 8-hour period. If diluted solution is not to be used within 6 hours, protect solution from
light. Do not dilute PLATINOL-AQ in just 5% Dextrose Injection. Adequate hydration
and urinary output must be maintained during the following 24 hours.
A repeat course of PLATINOL-AQ should not be given until the serum creatinine is
below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should
not be given until circulating blood elements are at an acceptable level (platelets
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
≥100,000/mm3, WBC ≥4000/mm3). Subsequent doses of PLATINOL-AQ should not be
given until an audiometric analysis indicates that auditory acuity is within normal limits.
PREPARATION OF INTRAVENOUS SOLUTIONS
Preparation Precautions
Caution should be exercised in handling the aqueous solution. Procedures for proper
handling and disposal of anticancer drugs should be utilized. Several guidelines on this
subject have been published.1-4 To minimize the risk of dermal exposure, always wear
impervious gloves when handling vials and IV sets containing PLATINOL-AQ.
Skin reactions associated with accidental exposure to cisplatin may occur. The use of
gloves is recommended. If PLATINOL-AQ contacts the skin or mucosa, immediately
and thoroughly wash the skin with soap and water and flush the mucosa with water. More
information is available in the references listed below.
Instructions for Preparation
The aqueous solution should be used intravenously only and should be administered by
IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
NOTE TO PHARMACIST: Exercise caution to prevent inadvertent PLATINOL-AQ
overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum
and flip-off seal of vial have been imprinted with the following statement:
CALL DR. IF DOSE>100 MG/M2/CYCLE.
STABILITY
PLATINOL-AQ is a sterile, multidose vial without preservatives.
Store at 15° C–25° C. Do not refrigerate. Protect unopened container from light.
The cisplatin remaining in the amber vial following initial entry is stable for 28 days
protected from light or for 7 days under fluorescent room light.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
PLATINOL®-AQ (cisplatin injection)
NDC 0015-3220-22—Each multidose vial contains 50 mg of cisplatin
NDC 0015-3221-22—Each multidose vial contains 100 mg of cisplatin
REFERENCES
1.
NIOSH Alert: Preventing occupational exposures to antineoplastic and other
hazardous drugs in healthcare settings. 2004. U.S. Department of Health and
Human Services, Public Health Service, Centers for Disease Control and
Prevention, National Institute for Occupational Safety and Health, DHHS
(NIOSH) Publication No. 2004-165.
2.
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling
occupational
exposure
to
hazardous
drugs.
OSHA,
1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.
3.
American Society of Health-System Pharmacists. ASHP guidelines on handling
hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4.
Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy
guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology
Nursing Society.
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
Rev May 2010
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:44:31.679334
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018057s079lbl.pdf', 'application_number': 18057, 'submission_type': 'SUPPL ', 'submission_number': 79}
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Rx only
PLATINOL®
(cisplatin for injection, USP)
WARNING
PLATINOL (cisplatin for injection, USP) should be administered under the supervision
of a qualified physician experienced in the use of cancer chemotherapeutic agents.
Appropriate management of therapy and complications is possible only when adequate
diagnostic and treatment facilities are readily available.
Cumulative renal toxicity associated with PLATINOL is severe. Other major dose-related
toxicities are myelosuppression, nausea, and vomiting.
Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus,
and/or loss of high frequency hearing and occasionally deafness, is significant.
Anaphylactic-like reactions to PLATINOL have been reported. Facial edema,
bronchoconstriction, tachycardia, and hypotension may occur within minutes of
PLATINOL administration. Epinephrine, corticosteroids, and antihistamines have been
effectively employed to alleviate symptoms (see WARNINGS and ADVERSE
REACTIONS).
Exercise caution to prevent inadvertent PLATINOL overdose. Doses greater than
100 mg/m2/cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid
inadvertent PLATINOL overdose due to confusion with PARAPLATIN® (carboplatin)
or prescribing practices that fail to differentiate daily doses from total dose per cycle.
DESCRIPTION
PLATINOL® (cisplatin for injection, USP) is a white to light yellow lyophilized powder.
Each vial of PLATINOL contains 50 mg cisplatin, 450 mg Sodium Chloride, USP, and
500 mg Mannitol, USP.
The active ingredient, cisplatin, is a yellow to orange crystalline powder with the
molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy
1
Reference ID: 3006561
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For current labeling information, please visit https://www.fda.gov/drugsatfda
metal complex containing a central atom of platinum surrounded by two chloride atoms
and two ammonia molecules in the cis position. It is soluble in water or saline at
1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207° C. chemical structure
CLINICAL PHARMACOLOGY
Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with
a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2
doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen
following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total body
clearances and volumes of distribution at steady-state for cisplatin are about 15 to
16 L/h/m2 and 11 to 12 L/m2.
Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to
chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups,
than to enzyme-catalyzed metabolism. At physiological pH in the presence of 0.1M
NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis
diammine platinum (II) in nearly equal concentrations. The latter, combined with the
possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or
proteins, accounts for the instability of cisplatin in biological matrices. The ratios of
cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between
patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.
Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins
that is characteristic of normal drug-protein binding. However, the platinum from
cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including
albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two
hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound.
The complexes between albumin and the platinum from cisplatin do not dissociate to a
significant extent and are slowly eliminated with a minimum half-life of five days or
more.
2
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest
in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and
spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is
present in tissues for as long as 180 days after the last administration. With the exception
of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower
than the concentrations in the organ where the tumor is located. Different metastatic sites
in the same patient may have different platinum concentrations. Hepatic metastases have
the highest platinum concentrations, but these are similar to the platinum concentrations
in normal liver. Maximum red blood cell concentrations of platinum are reached within
90 to 150 minutes after a 100 mg/m2 dose of cisplatin and decline in a biphasic manner
with a terminal half-life of 36 to 47 days.
Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions
varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered
platinum is excreted in the urine in 24 hours. Over five days following administration of
40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of
35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary
recoveries of platinum of about 14% to 30% of the dose are found following five daily
administrations of 20, 30, or 40 mg/m2/day. Only a small percentage of the administered
platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in
the urine in 24 hours is excreted within the first few hours. Platinum-containing species
excreted in the urine are the same as those found following the incubation of cisplatin
with urine from healthy subjects, except that the proportions are different.
The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of
the dose excreted within one hour after administration of 50 mg/m2. The mean renal
clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following
administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively.
The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular
filtration rate indicating that cisplatin or other platinum-containing molecules are actively
secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable
and is dependent on dose, urine flow rate, and individual variability in the extent of active
secretion and possible tubular reabsorption.
3
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There is a potential for accumulation of ultrafilterable platinum plasma concentrations
whenever cisplatin is administered on a daily basis but not when dosed on an intermittent
basis.
No significant relationships exist between the renal clearance of either free platinum or
cisplatin and creatinine clearance.
Although small amounts of platinum are present in the bile and large intestine after
administration of cisplatin, the fecal excretion of platinum appears to be insignificant.
INDICATIONS AND USAGE
PLATINOL (cisplatin for injection, USP) is indicated as therapy to be employed as
follows:
Metastatic Testicular Tumors
In established combination therapy with other approved chemotherapeutic agents in
patients with metastatic testicular tumors who have already received appropriate surgical
and/or radiotherapeutic procedures.
Metastatic Ovarian Tumors
In established combination therapy with other approved chemotherapeutic agents in
patients with metastatic ovarian tumors who have already received appropriate surgical
and/or radiotherapeutic procedures. An established combination consists of PLATINOL
and cyclophosphamide. PLATINOL, as a single agent, is indicated as secondary therapy
in patients with metastatic ovarian tumors refractory to standard chemotherapy who have
not previously received PLATINOL therapy.
Advanced Bladder Cancer
PLATINOL is indicated as a single agent for patients with transitional cell bladder cancer
which is no longer amenable to local treatments, such as surgery and/or radiotherapy.
CONTRAINDICATIONS
PLATINOL is contraindicated in patients with preexisting renal impairment. PLATINOL
should not be employed in myelosuppressed patients, or in patients with hearing
impairment.
4
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PLATINOL is contraindicated in patients with a history of allergic reactions to
PLATINOL or other platinum-containing compounds.
WARNINGS
PLATINOL (cisplatin for injection, USP) produces cumulative nephrotoxicity which is
potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen
(BUN), creatinine clearance, and magnesium, sodium, potassium, and calcium levels
should be measured prior to initiating therapy, and prior to each subsequent course. At
the recommended dosage, PLATINOL should not be given more frequently than once
every 3 to 4 weeks (see ADVERSE REACTIONS). Elderly patients may be more
susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).
There are reports of severe neuropathies in patients in whom regimens are employed
using higher doses of PLATINOL or greater dose frequencies than those recommended.
These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove
distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients
may be more susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric
Use).
Loss of motor function has also been reported.
Anaphylactic-like reactions to PLATINOL have been reported. These reactions have
occurred within minutes of administration to patients with prior exposure to PLATINOL,
and have been alleviated by administration of epinephrine, corticosteroids, and
antihistamines.
Since ototoxicity of PLATINOL is cumulative, audiometric testing should be performed
prior to initiating therapy and prior to each subsequent dose of drug (see ADVERSE
REACTIONS).
PLATINOL can cause fetal harm when administered to a pregnant woman. PLATINOL
is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue
culture. In mice PLATINOL is teratogenic and embryotoxic. If this drug is used during
pregnancy or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to the fetus. Patients should be advised to avoid
becoming pregnant.
5
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The carcinogenic effect of PLATINOL was studied in BD IX rats. PLATINOL was
administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body
weight per week. Four hundred and fifty-five days after the first application, 33 animals
died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma.
The development of acute leukemia coincident with the use of PLATINOL has been
reported. In these reports, PLATINOL was generally given in combination with other
leukemogenic agents.
Injection site reactions may occur during the administration of PLATINOL (see
ADVERSE REACTIONS). Given the possibility of extravasation, it is recommended to
closely monitor the infusion site for possible infiltration during drug administration. A
specific treatment for extravasation reactions is unknown at this time.
PRECAUTIONS
Peripheral blood counts should be monitored weekly. Liver function should be monitored
periodically. Neurologic examination should also be performed regularly (see
ADVERSE REACTIONS).
Drug Interactions
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin
therapy.
In a randomized trial in advanced ovarian cancer, response duration was adversely
affected
when
pyridoxine
was
used
in
combination
with
altretamine
(hexamethylmelamine) and PLATINOL.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See WARNINGS.
Pregnancy
Category D. See WARNINGS.
Nursing Mothers
Cisplatin has been reported to be found in human milk; patients receiving PLATINOL
should not breast-feed.
6
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Insufficient data are available from clinical trials of cisplatin in the treatment of
metastatic testicular tumors or advanced bladder cancer to determine whether elderly
patients respond differently than younger patients. In four clinical trials of combination
chemotherapy for advanced ovarian carcinoma, 1484 patients received cisplatin either in
combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than
65 years. In these trials, age was not found to be a prognostic factor for survival.
However, in a later secondary analysis for one of these trials, elderly patients were found
to have shorter survival compared with younger patients. In all four trials, elderly patients
experienced more severe neutropenia than younger patients. Higher incidences of severe
thrombocytopenia and leukopenia were also seen in elderly compared with younger
patients, although not in all cisplatin-containing treatment arms. In the two trials where
nonhematologic toxicity was evaluated according to age, elderly patients had a
numerically higher incidence of peripheral neuropathy than younger patients. Other
reported clinical experience suggests that elderly patients may be more susceptible to
myelosuppression, infectious complications, and nephrotoxicity than younger patients.
Cisplatin is known to be substantially excreted by the kidney and is contraindicated in
patients with preexisting renal impairment. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection, and renal function
should be monitored.
ADVERSE REACTIONS
Nephrotoxicity
Dose-related and cumulative renal insufficiency, including acute renal failure, is the
major dose-limiting toxicity of PLATINOL. Renal toxicity has been noted in 28% to 36%
of patients treated with a single dose of 50 mg/m2. It is first noted during the second week
after a dose and is manifested by elevations in BUN and creatinine, serum uric acid
and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and
severe with repeated courses of the drug. Renal function must return to normal
7
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
before another dose of PLATINOL can be given. Elderly patients may be more
susceptible to nephrotoxicity (see PRECAUTIONS: Geriatric Use).
Impairment of renal function has been associated with renal tubular damage. The
administration of PLATINOL using a 6- to 8-hour infusion with intravenous hydration,
and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can
occur after utilization of these procedures.
Ototoxicity
Ototoxicity has been observed in up to 31% of patients treated with a single dose of
PLATINOL 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high
frequency range (4000 to 8000 Hz). Decreased ability to hear normal conversational
tones may occur. Deafness after the initial dose of PLATINOL has been reported.
Ototoxic effects may be more severe in children receiving PLATINOL. Hearing loss can
be unilateral or bilateral and tends to become more frequent and severe with repeated
doses. Ototoxicity may be enhanced with prior or simultaneous cranial irradiation. It is
unclear whether PLATINOL-induced ototoxicity is reversible. Ototoxic effects may be
related to the peak plasma concentration of PLATINOL. Careful monitoring of
audiometry should be performed prior to initiation of therapy and prior to subsequent
doses of PLATINOL.
Vestibular toxicity has also been reported.
Ototoxicity may become more severe in patients being treated with other drugs with
nephrotoxic potential.
Hematologic
Myelosuppression occurs in 25% to 30% of patients treated with PLATINOL. The nadirs
in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with
most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia
are more pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g
hemoglobin/100 mL) occurs at approximately the same frequency and with the same
timing as leukopenia and thrombocytopenia. Fever and infection have also been reported
in patients with neutropenia. Potential fatalities due to infection (secondary to
myelosuppression) have been reported. Elderly patients may be more susceptible to
myelosuppression (see PRECAUTIONS: Geriatric Use).
8
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In addition to anemia secondary to myelosuppression, a Coombs’ positive hemolytic
anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course
of treatment may be accompanied by increased hemolysis and this risk should be
weighed by the treating physician.
The development of acute leukemia coincident with the use of PLATINOL has been
reported. In these reports, PLATINOL was generally given in combination with other
leukemogenic agents.
Gastrointestinal
Marked nausea and vomiting occur in almost all patients treated with PLATINOL, and
may be so severe that the drug must be discontinued. Nausea and vomiting may begin
within 1 to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting,
nausea and/or anorexia may persist for up to 1 week after treatment.
Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy)
has occurred in patients attaining complete emetic control on the day of PLATINOL
therapy.
Diarrhea has also been reported.
OTHER TOXICITIES
Vascular toxicities coincident with the use of PLATINOL in combination with other
antineoplastic agents have been reported. The events are clinically heterogeneous and
may
include
myocardial
infarction,
cerebrovascular
accident,
thrombotic
microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various
mechanisms have been proposed for these vascular complications. There are also reports
of Raynaud’s phenomenon occurring in patients treated with the combination of
bleomycin, vinblastine with or without PLATINOL. It has been suggested that
hypomagnesemia developing coincident with the use of PLATINOL may be an added,
although not essential, factor associated with this event. However, it is currently
unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying
vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any
of these factors.
9
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Serum Electrolyte Disturbances
Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia
have been reported to occur in patients treated with PLATINOL and are probably related
to renal tubular damage. Tetany has been reported in those patients with hypocalcemia
and hypomagnesemia. Generally, normal serum electrolyte levels are restored by
administering supplemental electrolytes and discontinuing PLATINOL.
Inappropriate antidiuretic hormone syndrome has also been reported.
Hyperuricemia
Hyperuricemia has been reported to occur at approximately the same frequency as the
increases in BUN and serum creatinine.
It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid
generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia
effectively reduces uric acid levels.
Neurotoxicity
See WARNINGS.
Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The
neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic
symptoms have been reported to occur after a single dose. Although symptoms and signs
of PLATINOL neuropathy usually develop during treatment, symptoms of neuropathy
may begin 3 to 8 weeks after the last dose of PLATINOL. PLATINOL therapy should be
discontinued when the symptoms are first observed. The neuropathy, however, may
progress further even after stopping treatment. Preliminary evidence suggests peripheral
neuropathy may be irreversible in some patients. Elderly patients may be more
susceptible to peripheral neuropathy (see PRECAUTIONS: Geriatric Use).
Lhermitte’s sign, dorsal column myelopathy, and autonomic neuropathy have also been
reported.
Loss
of
taste,
seizures,
leukoencephalopathy,
and
reversible
posterior
leukoencephalopathy syndrome (RPLS) have also been reported.
10
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of
sudden onset and short duration, have been reported and were usually associated in
patients receiving a relatively high cumulative dose of PLATINOL and with a relatively
advanced symptomatic stage of peripheral neuropathy.
Ocular Toxicity
Optic neuritis, papilledema, and cerebral blindness have been reported in patients
receiving standard recommended doses of PLATINOL. Improvement and/or total
recovery usually occurs after discontinuing PLATINOL. Steroids with or without
mannitol have been used; however, efficacy has not been established.
Blurred vision and altered color perception have been reported after the use of regimens
with higher doses of PLATINOL or greater dose frequencies than recommended in the
package insert. The altered color perception manifests as a loss of color discrimination,
particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular
retinal pigmentation of the macular area.
Anaphylactic-Like Reactions
Anaphylactic-like reactions have been reported in patients previously exposed to
PLATINOL. The reactions consist of facial edema, wheezing, tachycardia, and
hypotension within a few minutes of drug administration. Reactions may be controlled by
intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients
receiving PLATINOL should be observed carefully for possible anaphylactic-like
reactions and supportive equipment and medication should be available to treat such a
complication.
Hepatotoxicity
Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been
reported to be associated with PLATINOL administration at the recommended doses.
Other Events
Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia,
and dehydration have been reported.
Local soft tissue toxicity has been reported following extravasation of PLATINOL.
Severity of the local tissue toxicity appears to be related to the concentration of the
11
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PLATINOL solution. Infusion of solutions with a PLATINOL concentration greater than
0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.
OVERDOSAGE
Caution should be exercised to prevent inadvertent overdosage with PLATINOL.
Acute overdosage with this drug may result in kidney failure, liver failure, deafness,
ocular toxicity (including detachment of the retina), significant myelosuppression,
intractable nausea and vomiting and/or neuritis. In addition, death can occur following
overdosage.
No proven antidotes have been established for PLATINOL overdosage. Hemodialysis,
even when initiated four hours after the overdosage, appears to have little effect on
removing platinum from the body because of PLATINOL’s rapid and high degree of
protein binding. Management of overdosage should include general supportive measures
to sustain the patient through any period of toxicity that may occur.
DOSAGE AND ADMINISTRATION
PLATINOL is administered by slow intravenous infusion. PLATINOL SHOULD NOT
BE GIVEN BY RAPID INTRAVENOUS INJECTION.
Note: Needles or intravenous sets containing aluminum parts that may come in
contact with PLATINOL should not be used for preparation or administration.
Aluminum reacts with PLATINOL, causing precipitate formation and a loss of
potency.
Metastatic Testicular Tumors
The usual PLATINOL dose for the treatment of testicular cancer in combination with
other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.
Metastatic Ovarian Tumors
The usual PLATINOL dose for the treatment of metastatic ovarian tumors in combination
with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every 4 weeks (DAY 1).
The dose of cyclophosphamide when used in combination with PLATINOL is
600 mg/m2 IV once every 4 weeks (DAY 1).
12
Reference ID: 3006561
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
For directions for the administration of cyclophosphamide, refer to the cyclophosphamide
package insert.
In combination therapy, PLATINOL and cyclophosphamide are administered
sequentially.
As a single agent, PLATINOL should be administered at a dose of 100 mg/m2 IV per
cycle once every 4 weeks.
Advanced Bladder Cancer
PLATINOL should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per
cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation
therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of
50 mg/m2 per cycle repeated every 4 weeks is recommended.
All Patients
Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a
PLATINOL dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in
1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour
period. If diluted solution is not to be used within 6 hours, protect solution from light.
Adequate hydration and urinary output must be maintained during the following 24
hours.
A repeat course of PLATINOL should not be given until the serum creatinine is below
1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be
given until circulating blood elements are at an acceptable level (platelets ≥100,000/mm3,
WBC ≥4000/mm3). Subsequent doses of PLATINOL should not be given until an
audiometric analysis indicates that auditory acuity is within normal limits.
PREPARATION OF INTRAVENOUS SOLUTIONS
Preparation Precautions
Caution should be exercised in handling the powder and preparing the solution of
cisplatin. Procedures for proper handling and disposal of anticancer drugs should be
utilized. Several guidelines on this subject have been published.1-4 To minimize the risk
13
Reference ID: 3006561
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For current labeling information, please visit https://www.fda.gov/drugsatfda
of dermal exposure, always wear impervious gloves when handling vials and IV sets
containing PLATINOL for injection.
Skin reactions associated with accidental exposure to cisplatin may occur. The use of
gloves is recommended. If PLATINOL powder or PLATINOL solution contacts the skin
or mucosa, immediately and thoroughly wash the skin with soap and water and flush the
mucosa with water. More information is available in the references listed below.
Instructions for Preparation
The 50 mg vials should be reconstituted with 50 mL of Sterile Water for Injection, USP.
Each mL of the resulting solution will contain 1 mg of PLATINOL.
Reconstitution as recommended results in a clear, colorless to slight yellow solution.
The reconstituted solution should be used intravenously only and should be administered
by IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
NOTE TO PHARMACIST: Exercise caution to prevent inadvertent PLATINOL
overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum
and flip-off seal of vial have been imprinted with the following statement:
CALL DR. IF DOSE>100 MG/M2/CYCLE.
STABILITY
Unopened vials of dry powder are stable for the lot life indicated on the package when
stored at room temperature (25° C, 77° F).
The reconstituted solution is stable for 20 hours at room temperature (25° C, 77° F).
Solution removed from the amber vial should be protected from light if it is not to be
used within six hours.
Important Note: Once reconstituted, the solution should be kept at room temperature
(25° C, 77° F). If the reconstituted solution is refrigerated a precipitate will form.
14
Reference ID: 3006561
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
PLATINOL® (cisplatin for injection, USP)
NDC 0015-3072-20—Each amber vial contains 50 mg of cisplatin
REFERENCES
1.
NIOSH Alert: Preventing occupational exposures to antineoplastic and other
hazardous drugs in healthcare settings. 2004. U.S. Department of Health and
Human Services, Public Health Service, Centers for Disease Control and
Prevention, National Institute for Occupational Safety and Health, DHHS
(NIOSH) Publication No. 2004-165.
2.
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling
occupational
exposure
to
hazardous
drugs.
OSHA,
1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.
3.
American Society of Health-System Pharmacists. ASHP guidelines on handling
hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4.
Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy
guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology
Nursing Society.
Manufactured for:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
Made in Italy
1192978A2
Rev September 2010
15
Reference ID: 3006561
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2025-02-12T13:44:31.774903
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018057s080lbl.pdf', 'application_number': 18057, 'submission_type': 'SUPPL ', 'submission_number': 80}
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CISplatin Injection
Rx only
WARNING
Cisplatin Injection should be administered under the supervision of a qualified physician
experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy
and complications is possible only when adequate diagnostic and treatment facilities are
readily available.
Cumulative renal toxicity associated with cisplatin is severe. Other major dose-related
toxicities are myelosuppression, nausea, and vomiting.
Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus, and/or
loss of high frequency hearing and occasionally deafness, is significant.
Anaphylactic-like reactions to cisplatin have been reported. Facial edema, bronchoconstriction,
tachycardia, and hypotension may occur within minutes of cisplatin administration.
Epinephrine, corticosteroids, and antihistamines have been effectively employed to alleviate
symptoms (see WARNINGS and ADVERSE REACTIONS sections).
Exercise caution to prevent inadvertent cisplatin overdose. Doses greater than 100
mg/m2/cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid inadvertent
cisplatin overdose due to confusion with carboplatin or prescribing practices that fail to
differentiate daily doses from total dose per cycle.
DESCRIPTION
Cisplatin Injection infusion concentrate is a clear, colorless, sterile aqueous solution available in
amber vials. Each 50 mL or 100 mL amber vial of infusion concentrate contains: 1 mg/mL
cisplatin, 9 mg/mL sodium chloride, hydrochloric acid and sodium hydroxide to approximate pH
of 4.0, and water for injection to a final volume of 50 mL or 100 mL, respectively.
Cisplatin Injection infusion concentrate must be further diluted prior to administration (see
DOSAGE AND ADMINISTRATION, All Patients).
The active ingredient, cisplatin, is a yellow to orange crystalline powder with the molecular
formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy metal complex
containing a central atom of platinum surrounded by two chloride atoms and two ammonia
molecules in the cis position. It is soluble in water or saline at 1 mg/mL and in
dimethylformamide at 24 mg/mL. It has a melting point of 207° C. structural formula
CLINICAL PHARMACOLOGY
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Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with a half-
life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2 doses.
Monoexponential decay and plasma half-lives of about 0.5 hour are also seen following 2-hour or
7-hour infusions of 100 mg/m2. After the latter, the total-body clearances and volumes of
distribution at steady-state for cisplatin are about 15 to 16 L/h/m2 and 11 to 12 L/m2 .
Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to chemical
displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-
catalyzed metabolism. At physiological pH in the presence of 0.1M NaCl, the predominant
molecular species are cisplatin and monohydroxymonochloro cis-diammine platinum (II) in
nearly equal concentrations. The latter, combined with the possible direct displacement of the
chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the instability of
cisplatin in biological matrices. The ratios of cisplatin to total free (ultrafilterable) platinum in the
plasma vary considerably between patients and range from 0.5 to 1.1 after a dose of 100 mg/m2 .
Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is
characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not
cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and
gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour
infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the
platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a
minimum half-life of five days or more.
Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest in liver,
prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and
lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for
as long as 180 days after the last administration. With the exception of intracerebral tumors,
platinum concentrations in tumors are generally somewhat lower than the concentrations in the
organ where the tumor is located. Different metastatic sites in the same patient may have different
platinum concentrations. Hepatic metastases have the highest platinum concentrations, but these
are similar to the platinum concentrations in normal liver. Maximum red blood cell
concentrations of platinum are reached within 90 to 150 minutes after a 100 mg/m2 dose of
cisplatin and decline in a biphasic manner with a terminal half-life of 36 to 47 days.
Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions varying
in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is
excreted in the urine in 24 hours. Over five days following administration of 40 to 100 mg/m2
doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of 35% to 51% of the dosed
platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to
30% of the dose are found following five daily administrations of 20, 30, or 40 mg/m2/day. Only
a small percentage of the administered platinum is excreted beyond 24 hours post-infusion and
most of the platinum excreted in the urine in 24 hours is excreted within the first few hours.
Platinum-containing species excreted in the urine are the same as those found following the
incubation of cisplatin with urine from healthy subjects, except that the proportions are different.
The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose
excreted within one hour after administration of 50 mg/m2. The mean renal clearance of cisplatin
exceeds creatinine clearance and is 62 and 50 mL/min/m2 following administration of 100 mg/m2
as 2-hour or 6- to 7-hour infusions, respectively.
The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate
indicating that cisplatin or other platinum-containing molecules are actively secreted by the
kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose,
urine flow rate, and individual variability in the extent of active secretion and possible tubular
reabsorption.
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There is a potential for accumulation of ultrafilterable platinum plasma concentrations whenever
cisplatin is administered on a daily basis but not when dosed on an intermittent basis.
No significant relationships exist between the renal clearance of either free platinum or cisplatin
and creatinine clearance.
Although small amounts of platinum are present in the bile and large intestine after administration
of cisplatin, the fecal excretion of platinum appears to be insignificant.
INDICATIONS
Cisplatin Injection is indicated as therapy to be employed as follows:
Metastatic Testicular Tumors
In established combination therapy with other approved chemotherapeutic agents in patients with
metastatic testicular tumors who have already received appropriate surgical and/or
radiotherapeutic procedures.
Metastatic Ovarian Tumors
In established combination therapy with other approved chemotherapeutic agents in patients with
metastatic ovarian tumors who have already received appropriate surgical and/or radiotherapeutic
procedures. An established combination consists of Cisplatin Injection and cyclophosphamide.
Cisplatin Injection, as a single agent, is indicated as secondary therapy in patients with metastatic
ovarian tumors refractory to standard chemotherapy who have not previously received Cisplatin
Injection therapy.
Advanced Bladder Cancer
Cisplatin Injection is indicated as a single agent for patients with transitional cell bladder cancer
which is no longer amenable to local treatments, such as surgery and/or radiotherapy.
CONTRAINDICATIONS
Cisplatin is contraindicated in patients with preexisting renal impairment. Cisplatin should not be
employed in myelosuppressed patients, or in patients with hearing impairment.
Cisplatin is contraindicated in patients with a history of allergic reactions to cisplatin or other
platinum-containing compounds.
WARNINGS
Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics.
The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and magnesium, sodium,
potassium, and calcium levels should be measured prior to initiating therapy, and prior to each
subsequent course. At the recommended dosage, cisplatin should not be given more frequently
than once every 3 to 4 weeks (see ADVERSE REACTIONS). Elderly patients may be more
susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use).
There are reports of severe neuropathies in patients in whom regimens are employed using higher
doses of cisplatin or greater dose frequencies than those recommended. These neuropathies may
be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of
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proprioception and vibratory sensation. Elderly patients may be more susceptible to peripheral
neuropathy (see PRECAUTIONS, Geriatric Use).
Loss of motor function has also been reported.
Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within
minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by
administration of epinephrine, corticosteroids, and antihistamines.
Cisplatin can commonly cause ototoxicity which is cumulative and may be severe. Audiometric
testing should be performed prior to initiating therapy and prior to each subsequent dose of drug
(see ADVERSE REACTIONS).
All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each
subsequent dose, of drug and for several years post therapy.
Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic in
bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin
is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Patients should be advised to avoid becoming pregnant.
The carcinogenic effect of cisplatin was studied in BD IX rats. Cisplatin was administered
intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body weight per week. Four
hundred and fifty-five days after the first application, 33 animals died, 13 of them related to
malignancies: 12 leukemias and 1 renal fibrosarcoma.
The development of acute leukemia coincident with the use of cisplatin has been reported. In
these reports, cisplatin was generally given in combination with other leukemogenic agents.
Injection site reactions may occur during the administration of cisplatin (see ADVERSE
REACTIONS). Given the possibility of extravasation, it is recommended to closely monitor the
infusion site for possible infiltration during drug administration. A specific treatment for
extravasation reactions is unknown at this time.
PRECAUTIONS
Peripheral blood counts should be monitored weekly. Liver function should be monitored
periodically. Neurologic examination should also be performed regularly (see ADVERSE
REACTIONS).
Drug Interactions
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy.
In a randomized trial in advanced ovarian cancer, response duration was adversely affected when
pyridoxine was used in combination with altretamine (hexamethylmelamine) and cisplatin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See WARNINGS.
Pregnancy
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Pregnancy Category D
See WARNINGS.
Nursing Mothers
Cisplatin has been reported to be found in human milk; patients receiving cisplatin should not
breast-feed.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
All children should have audiometric monitoring performed prior to initiation of therapy prior to
each subsequent dose, and for several years post therapy. Advanced testing methods may allow
for earlier detection of hearing loss in an attempt to facilitate the rapid initiation of interventions
that can limit the potential adverse impact of hearing impairment on a child's cognitive and social
development.
Geriatric Use
Insufficient data are available from clinical trials of cisplatin in the treatment of metastatic
testicular tumors or advanced bladder cancer to determine whether elderly patients respond
differently than younger patients. In four clinical trials of combination chemotherapy for
advanced ovarian carcinoma, 1484 patients received cisplatin either in combination with
cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than 65 years. In these trials, age
was not found to be a prognostic factor for survival. However, in a later secondary analysis for
one of these trials, elderly patients were found to have shorter survival compared with younger
patients. In all four trials, elderly patients experienced more severe neutropenia than younger
patients. Higher incidences of severe thrombocytopenia and leukopenia were also seen in elderly
compared with younger patients, although not in all cisplatin-containing treatment arms. In the
two trials where nonhematologic toxicity was evaluated according to age, elderly patients had a
numerically higher incidence of peripheral neuropathy than younger patients. Other reported
clinical experience suggests that elderly patients may be more susceptible to myelosuppression,
infectious complications, and nephrotoxicity than younger patients.
Cisplatin is known to be substantially excreted by the kidney and is contraindicated in patients
with preexisting renal impairment. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and renal function should be monitored.
ADVERSE REACTIONS
Nephrotoxicity
Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-
limiting toxicity of cisplatin. Renal toxicity has been noted in 28% to 36% of patients treated with
a single dose of 50 mg/m2. It is first noted during the second week after a dose and is manifested
by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance.
Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal
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function must return to normal before another dose of cisplatin can be given. Elderly
patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use).
Impairment of renal function has been associated with renal tubular damage. The administration
of cisplatin using a 6- to 8-hour infusion with intravenous hydration, and mannitol has been used
to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of these
procedures.
Ototoxicity
Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50
mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to
8000 Hz). The prevelance of hearing loss in children is particularly high and is estimated to be
40-60%. Decreased ability to hear normal conversational tones may occur. Deafness after the
initial dose of cisplatin has been reported. Ototoxic effects may be more severe in children
receiving cisplatin.
Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with
repeated cisplatin doses. It is unclear whether cisplatin-induced ototoxicity is reversible.
Vestibular toxicity has also been reported. Ototoxic effects may be related to the peak plasma
concentration of cisplatin. Ototoxicity can occur during treatment or be delayed. Audiometric
monitoring should be performed prior to initiation of therapy, prior to each subsequent dose, and
for several years post therapy.
The risk of ototoxicity may be increased by prior or simultaneous cranial irradiation, and may be
more severe in patients less than 5 years of age, patients being treated with other ototoxic drugs
(e.g. aminoglycosides and vancomycin), and in patients with renal impairment.
Genetic factors (e.g. variants in the thiopurine S-methyltransferase [TPMT] gene) may contribute
to cisplatin-induced ototoxicity; although this association has not been consistent across
populations and study designs.
Hematologic
Myelosuppression occurs in 25% to 30% of patients treated with cisplatin. The nadirs in
circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most
patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more
pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at
approximately the same frequency and with the same timing as leukopenia and
thrombocytopenia. Fever and infection have also been reported in patients with neutropenia.
Potential fatalities due to infection (secondary to myelosuppression) have been reported. Elderly
patients may be more susceptible to myelosuppression (see PRECAUTIONS, Geriatric Use).
In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has
been reported. In the presence of cisplatin hemolytic anemia, a further course of treatment may be
accompanied by increased hemolysis and this risk should be weighed by the treating physician.
The development of acute leukemia coincident with the use of cisplatin has been reported. In
these reports, cisplatin was generally given in combination with other leukemogenic agents.
Gastrointestinal
Marked nausea and vomiting occur in almost all patients treated with cisplatin, and may be so
severe that the drug must be discontinued. Nausea and vomiting may begin within 1 to 4 hours
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after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anorexia may
persist for up to 1 week after treatment.
Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has
occurred in patients attaining complete emetic control on the day of cisplatin therapy.
Diarrhea has also been reported.
To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562
4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
OTHER TOXICITIES
Vascular toxicities coincident with the use of cisplatin in combination with other antineoplastic
agents have been reported. The events are clinically heterogeneous and may include myocardial
infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome
[HUS]), or cerebral arteritis. Various mechanisms have been proposed for these vascular
complications. There are also reports of Raynaud's phenomenon occurring in patients treated with
the combination of bleomycin, vinblastine with or without cisplatin. It has been suggested that
hypomagnesemia developing coincident with the use of cisplatin may be an added, although not
essential, factor associated with this event. However, it is currently unknown if the cause of
Raynaud's phenomenon in these cases is the disease, underlying vascular compromise,
bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.
Serum Electrolyte Disturbances
Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been
reported to occur in patients treated with cisplatin and are probably related to renal tubular
damage. Tetany has been reported in those patients with hypocalcemia and hypomagnesemia.
Generally, normal serum electrolyte levels are restored by administering supplemental
electrolytes and discontinuing cisplatin.
Inappropriate antidiuretic hormone syndrome has also been reported.
Hyperuricemia
Hyperuricemia has been reported to occur at approximately the same frequency as the increases
in BUN and serum creatinine.
It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid generally
occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively
reduces uric acid levels.
Neurotoxicity
See WARNINGS.
Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The
neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic
symptoms have been reported to occur after a single dose. Although symptoms and signs of
cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8
weeks after the last dose of cisplatin. Cisplatin therapy should be discontinued when the
symptoms are first observed. The neuropathy, however, may progress further even after stopping
treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some
patients. Elderly patients may be more susceptible to peripheral neuropathy (see
PRECAUTIONS, Geriatric Use).
Lhermitte's sign, dorsal column myelopathy, and autonomic neuropathy have also been reported.
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Loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy
syndrome (RPLS) have also been reported.
Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden
onset and short duration, have been reported and were usually associated in patients receiving a
relatively high cumulative dose of cisplatin and with a relatively advanced symptomatic stage of
peripheral neuropathy.
Ocular Toxicity
Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving
standard recommended doses of cisplatin. Improvement and/or total recovery usually occurs after
discontinuing cisplatin. Steroids with or without mannitol have been used; however, efficacy has
not been established.
Blurred vision and altered color perception have been reported after the use of regimens with
higher doses of cisplatin or greater dose frequencies than recommended in the package insert. The
altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow
axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area.
Anaphylactic-Like Reactions
Anaphylactic-like reactions have been reported in patients previously exposed to cisplatin. The
reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes
of drug administration. Reactions may be controlled by intravenous epinephrine with
corticosteroids and/or antihistamines as indicated. Patients receiving cisplatin should be observed
carefully for possible anaphylactic-like reactions and supportive equipment and medication
should be available to treat such a complication.
Hepatotoxicity
Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported
to be associated with cisplatin administration at the recommended doses.
Other Events
Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and
dehydration have been reported.
Local soft tissue toxicity has been reported following extravasation of cisplatin. Severity of the
local tissue toxicity appears to be related to the concentration of the cisplatin solution. Infusion of
solutions with a cisplatin concentration greater than 0.5 mg/mL may result in tissue cellulitis,
fibrosis, necrosis, pain, edema, and erythema.
OVERDOSAGE
Caution should be exercised to prevent inadvertent overdosage with cisplatin. Acute
overdosage with this drug may result in kidney failure, liver failure, deafness, ocular toxicity
(including detachment of the retina), significant myelosuppression, intractable nausea and
vomiting and/or neuritis. In addition, death can occur following overdosage.
Reference ID: 3708516
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No proven antidotes have been established for cisplatin overdosage. Hemodialysis, even when
initiated four hours after the overdosage, appears to have little effect on removing platinum from
the body because of cisplatin's rapid and high degree of protein binding. Management of
overdosage should include general supportive measures to sustain the patient through any period
of toxicity that may occur.
DOSAGE AND ADMINISTRATION
Cisplatin Injection is administered by slow intravenous infusion. CISPLATIN INJECTION
SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.
Note: Needles or intravenous sets containing aluminum parts that may come in contact with
Cisplatin Injection should not be used for preparation or administration. Aluminum reacts
with Cisplatin Injection, causing precipitate formation and a loss of potency.
Metastatic Testicular Tumors
The usual Cisplatin Injection dose for the treatment of testicular cancer in combination with other
approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.
Metastatic Ovarian Tumors
The usual Cisplatin Injection dose for the treatment of metastatic ovarian tumors in combination
with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every four weeks (DAY 1).
The dose of cyclophosphamide when used in combination with Cisplatin Injection is 600 mg/m2
IV once every 4 weeks (DAY 1).
For directions for the administration of cyclophosphamide, refer to the cyclophosphamide
package insert.
In combination therapy, Cisplatin Injection and cyclophosphamide are administered sequentially.
As a single agent, Cisplatin Injection should be administered at a dose of 100 mg/m2 IV per cycle
once every four weeks.
Advanced Bladder Cancer
Cisplatin Injection should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per
cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy
and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle
repeated every 4 weeks is recommended.
All Patients
Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a Cisplatin
Injection dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3
normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour period. If diluted
solution is not to be used within 6 hours, protect solution from light. Do not dilute Cisplatin
Injection in just 5% Dextrose Injection. Adequate hydration and urinary output must be
maintained during the following 24 hours.
A repeat course of Cisplatin Injection should not be given until the serum creatinine is below 1.5
mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until
circulating blood elements are at an acceptable level (platelets ≥100,000/mm3, WBC
Reference ID: 3708516
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≥4000/mm3). Subsequent doses of Cisplatin Injection should not be given until an audiometric
analysis indicates that auditory acuity is within normal limits.
PREPARATION OF INTRAVENOUS SOLUTIONS
Preparation Precautions
Caution should be exercised in handling the aqueous solution. Procedures for proper handling and
disposal of anticancer drugs should be utilized. Several guidelines on this subject have been
published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when
handling vials and IV sets containing cisplatin.
Skin reactions associated with accidental exposure to cisplatin may occur. The use of gloves is
recommended. If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the
skin with soap and water and flush the mucosa with water. More information is available in the
references listed below.
Instructions for Preparation
The aqueous solution should be used intravenously only and should be administered by IV
infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
NOTE TO PHARMACIST: Exercise caution to prevent inadvertent cisplatin overdosage. Please
call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum and flip-off seal of vial
have been imprinted with the following statement: CALL DR. IF DOSE>100 MG/M2/CYCLE.
STABILITY
Cisplatin Injection is a sterile, multidose vial without preservatives.
Store at 15° C to 25°C (59° to 77°F). Do not refrigerate. Protect unopened container from
light.
The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected
from light or for 7 days under fluorescent room light.
HOW SUPPLIED
Cisplatin Injection is available as follows:
NDC 44567-509-01 Each multidose vial contains 50 mg of cisplatin
NDC 44567-510-01 Each multidose vial contains 100 mg of cisplatin
REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs
in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health
Service, Centers for Disease Control and Prevention, National Institute for Occupational
Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
Reference ID: 3708516
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2.
Controlling occupational exposure to hazardous drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous
drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines
and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.
Manufactured for:
WG Critical Care, LLC
Paramus, NJ 07652
Made in Italy
Rev. 02/2015
Reference ID: 3708516
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018057s083lbl.pdf', 'application_number': 18057, 'submission_type': 'SUPPL ', 'submission_number': 83}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
THERESA M MICHELE
03/25/2014
Reference ID: 3476794
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018060Orig1s066lbl.pdf', 'application_number': 18060, 'submission_type': 'SUPPL ', 'submission_number': 66}
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PV 1354-A UCP
Cinobac®
Cinoxacin, USP
DESCRIPTION
Cinobac® (Cinoxacin, USP) is a synthetic antibacterial agent for oral administration. Cinoxacin,
a quinolone, is 1-ethyl-1,4-dihydro-4-oxo-[1,3] dioxolo [4,5-g] cinnoline-3-carboxylic acid and
occurs as white or very light-yellow, needle-shaped crystals. Cinobac is available as 250- (0.95
mmol) and 500-mg (1.9 mmol) capsules. These capsules also contain D & C Yellow No. 10, F D
& C Blue No. 1, F D & C Red No. 3, F D & C Yellow No. 6, gelatin, silicon dioxide, silicone
fluid, sodium lauryl sulfate, starch, titanium dioxide, and other inactive ingredients.
The molecular formula is C12H10N2O5 and the molecular weight is 262.22. The structural
formula is:
N
N
COOH
O
O
O
CH2CH3
CLINICAL PHARMACOLOGY
Cinoxacin is rapidly absorbed after oral administration. In fluorometric assay, a 500-mg dose
produced a peak serum concentration of 15 µg/mL, which declined to approximately 1 to 2
µg/mL 6 hours after administration. A 500-mg dose produced an average urine concentration of
approximately 300 µg/mL during the first 4 hours and approximately 100 µg/mL during the
second 4-hour period. These urine concentrations are many times greater than the minimal
inhibitory concentration (MIC) of cinoxacin for most gram-negative organisms commonly found
in urinary tract infections.
Ninety-seven percent of a 500-mg oral dose of radiolabeled cinoxacin was recovered in the
urine within 24 hours, 60% of which was present as unaltered cinoxacin and the remainder as
inactive metabolic products.
The presence of food did not affect the total absorption of cinoxacin. Peak serum
concentrations were reduced by 30%, but the 24-hour urinary recovery of antibacterial activity
was unaltered. The mean serum half-life is 1.5 hours.
Geriatric--Twenty geriatric patients (ages 70-89, 14 men and 6
women) with creatinine clearance from 58-80 mL/min, were
given cinoxacin 500 mg every 12 hours for 7 days. Following
the first dose of cinoxacin, the mean peak of the serum
concentration was 14 µg/mL. Following the last dose, the mean
peak of the serum concentration was 15 µg/mL. The mean urine
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Cinobac® (Cinoxacin, USP)
2
concentration after 3 hours was 656 µg/mL, at 3-6 hr 1,234
µg/mL, and at 12 hours 33 µg/mL. The mean recovery of
unaltered cinoxacin from the urine following the first dose and
last dose was 55% and 62%, respectively.
Microbiology--Cinoxacin has in vitro activity against many gram-negative aerobic bacteria,
particularly strains of Enterobacteriaceae. Cinoxacin inhibits bacterial deoxyribonucleic acid
(DNA) synthesis, is bactericidal, and is active over the entire urinary pH range. Cross-resistance
with nalidixic acid has been demonstrated.
Conventional chromosomal resistance to cinoxacin taken at recommended doses has been
reported to emerge in approximately 4% of patients during treatment; however, bacterial
resistance to cinoxacin has not been shown to be transferable via R-factor. Cinoxacin has been
shown to be active against most strains of the following organisms both in vitro and in clinical
infections (see Indications and Usage):
Gram-negative aerobes:
Enterobacter species
Escherichia coli
Klebsiella species
Proteus mirabilis
Proteus vulgaris
Note: Enterococcus species, Pseudomonas species, and Staphylococcus species are resistant.
Susceptibility Tests--Diffusion Techniques: Quantitative methods that require measurement
of zone diameters give an estimate of bacterial susceptibility. One such procedure is the National
Committee for Clinical Laboratory Standards (NCCLS) approved procedure (M2-A5--
Performance Standards for Antimicrobial Disk Susceptibility Tests 1993).1 This method has been
recommended for use with the 100-µg cinoxacin disk to test susceptibility to cinoxacin.
Interpretation involves correlation of the diameters obtained in the disk test with minimum
inhibitory concentrations (MIC) for cinoxacin. Reports from the laboratory giving results of the
standard single-disk susceptibility test with a 100-µg cinoxacin disk should be interpreted
according to the following criteria (these criteria only apply to isolates from urinary tract
infections):
Zone diameter (mm)
Interpretation
≥19
(S) Susceptible
15-18
(I) Intermediate
≤14
(R) Resistant
A report of "susceptible" indicates that the pathogen is likely to be inhibited by generally
achievable urine levels. A report of "intermediate" indicates that the test results be considered
equivocal or indeterminate. A report of "resistant" indicates that achievable concentrations of the
antibiotic are unlikely to be inhibitory and other therapy should be selected.
Certain strains of Enterobacteriaceae exhibit heterogeneity of resistance to cinoxacin. These
strains produce isolated colonies within the inhibition zone. When such strains are encountered,
the clear inhibition zone should be measured within the isolated colonies.
Standardized procedures require the use of laboratory control organisms. The 100-µg cinoxacin
disk should give the following zone diameter:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Cinobac® (Cinoxacin, USP)
3
Organism
Zone diameter (mm)
E. coli ATCC 25922
26-32
Other quinolone antibacterial disks should not be substituted when performing susceptibility
tests for cinoxacin because of spectrum differences between cinoxacin and other quinolones. The
100-µg cinoxacin disk should be used for all in vitro testing of isolates.
Dilution Techniques: Broth and agar dilution methods, such as those recommended by the
NCCLS (M7-A3--Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that
Grow Aerobically 1993), may be used to determine the MIC of cinoxacin.2 MIC test results
should be interpreted according to the following criteria (these criteria only apply to isolates
from urinary tract infections):
MIC (µg/mL)
Interpretation
≤16
(S) Susceptible
32
(I) Intermediate
≥64
(R) Resistant
As with standard diffusion methods, dilution procedures require the use of laboratory control
organisms. Standard cinoxacin powder should give the following MIC values:
Organism
MIC range (µg/mL)
E. coli ATCC 25922
2.0-8.0
INDICATIONS AND USAGE
Cinobac is indicated for the treatment of initial and recurrent urinary tract infections in adults
caused by the following susceptible microorganisms: Escherichia coli, Proteus mirabilis,
Proteus vulgaris, Klebsiella species (including K. pneumoniae), and Enterobacter species.
Cinobac is effective in preventing urinary tract infections for up to 5 months in women with a
history of recurrent urinary tract infections.
In vitro susceptibility testing should be performed prior to administration of the drug and, when
clinically indicated, during treatment.
CONTRAINDICATION
Cinobac is contraindicated in patients with a history of hypersensitivity to cinoxacin or other
quinolones.
WARNINGS
THE SAFETY AND EFFECTIVENESS OF CINOXACIN IN PEDIATRIC PATIENTS,
PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN
ESTABLISHED. (SEE PEDIATRIC USE, PREGNANCY, AND NURSING MOTHERS
SUBSECTIONS IN THE PRECAUTIONS SECTIONS). The oral administration of a single
250-mg/kg dose of cinoxacin causes lameness in immature dogs. Histopathological examination
of the weight-bearing joints of these dogs revealed lesions of the cartilage. Other quinolones also
produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature
animals of various species.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the
first dose, have been reported in patients receiving quinolone class antimicrobials. Some
reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling,
pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cinobac® (Cinoxacin, USP)
4
previous hypersensitivity reactions. If an allergic reaction to cinoxacin occurs, discontinue the
drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other
resuscitative measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines, and airway management as clinically indicated.
Convulsions and abnormal electroencephalograms have been reported in a few patients
receiving quinolone class antimicrobials. No causal relationship has been established.
Convulsions, increased intracranial pressure, and toxic psychoses have also been reported in
patients receiving other drugs in this class.
Quinolones may also cause central nervous system (CNS) stimulation with tremors,
restlessness, light-headedness, confusion, or hallucinations. If these reactions occur in patients
receiving cinoxacin, the drug should be discontinued and appropriate measures instituted. As
with all quinolones, cinoxacin should be used with caution in patients with known or suspected
CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors that
predispose to seizures (see Adverse Reactions).
Achilles and other tendon ruptures that require surgical repair
or resulted in prolonged disability have been reported with
quinolones. Cinoxacin should be discontinued if the patient
experiences pain, inflammation, or tendon rupture.
PRECAUTIONS
General--Since Cinobac is eliminated primarily by the kidney, the usual dosage should be
lower in patients with reduced renal function (see Dosage and Administration). Administration of
Cinobac is not recommended for anuric patients.
In clinical trials with large doses of quinolones, crystalluria was reported in some volunteers.
Although crystalluria is not expected to occur with the usually recommended dosages of
cinoxacin, patients should be well hydrated, and alkalinization of urine should be avoided.
Moderate to severe phototoxicity reactions have been observed in patients who were exposed
to direct sunlight while receiving some members of this drug class. Excessive sunlight should be
avoided. Therapy should be discontinued if phototoxicity occurs.
As with any potent drug, periodic assessment of organ system function, including renal,
hepatic, and hematopoietic function, is advisable during prolonged therapy.
Information for Patients--Patients should be advised that cinoxacin may be taken with or
without meals. Patients should drink fluids liberally. Antacids containing
magnesium or aluminum, as well as sucralfate, metal cations
such as iron, and multivitamin preparations with zinc or
VIDEX (didanosine) chewable/buffered tablets or the
pediatric powder for oral solution may interfere with the
gastrointestinal absorption of cinoxacin. These agents should be
taken at least 2 hours before or 2 hours after cinoxacin
administration. Since sucralfate or antacids affect the absorption
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cinobac® (Cinoxacin, USP)
5
of certain quinolones, patients should not take sucralfate or
antacids within 2 hours of the administration of cinoxacin.
Patients should be advised to avoid excessive sunlight during cinoxacin therapy. If
phototoxicity occurs, cinoxacin therapy should be discontinued.
Cinoxacin may be associated with hypersensitivity reactions following even a single dose. The
drug should be discontinued at the first sign of skin rash or allergic reaction.
Cinoxacin can cause dizziness and light-headedness; therefore, patients should know how they
react to the drug before operating an automobile or machinery or engaging in an activity
requiring mental alertness or coordination.
Patients should be advised that convulsions have been reported
in patients taking quinolones, including cinoxacin acid, and to
notify their physician before taking this drug if there is a history
of this condition.
Patients should be advised that cinoxacin may increase the effects of theophylline and caffeine.
There is a possibility of caffeine accumulation when products containing caffeine are consumed
during cinoxacin therapy.
Drug Interactions--Elevated plasma levels of theophylline have been reported with
concomitant use of some quinolones. There have been reports of theophylline-related side-effects
in patients on concomitant theophylline-quinolone therapy. Therefore, monitoring of theophylline
plasma levels should be considered and dosage of theophylline adjusted as required.
Quinolones have also been shown to interfere with the metabolism of caffeine. This may lead
to reduced clearance of caffeine and a prolongation of its plasma half-life. Although this
interaction has not been reported with cinoxacin, caution should be exercised when cinoxacin is
given concomitantly with caffeine-containing products.
Antacids or sucralfate substantially interfere with the absorption of some quinolones, resulting
in low urine levels. Also, concomitant administration of quinolones with products containing
iron, or multivitamins containing zinc, or Videx (didanosine)
chewable/buffered tablets or the pediatric powder for oral
solution may result in low urine levels.
Quinolones, including cinoxacin, may enhance the effects of oral anticoagulants, such as
warfarin or its derivatives. When these products are administered concomitantly, prothrombin
time or other suitable coagulation tests should be closely monitored.
Seizures have been reported in patients taking another quinolone class antimicrobial and the
nonsteroidal anti-inflammatory drug fenbufen concurrently. Animal studies also suggest an
increased potential for seizures when these 2 drugs are given concomitantly. Fenbufen is not
approved in the United States at this time. Physicians are provided this information to increase
awareness of the potential for serious interactions when cinoxacin and certain nonsteroidal anti-
inflammatory agents are administered concomitantly.
Elevated cyclosporine serum levels have been reported with the concomitant use of quinolones
and cyclosporine.
Pregnancy--Teratogenic Effects--Pregnancy Category C--Reproduction studies have been
performed in rats and rabbits at doses up to 10 times the daily human dose and have revealed no
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cinobac® (Cinoxacin, USP)
6
evidence of impaired fertility or harm to the fetus due to cinoxacin. There are, however, no
adequate and well-controlled studies in pregnant women. Cinoxacin should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus (see Warnings).
Nursing Mothers--It is not known whether cinoxacin is excreted in human milk. Because other
drugs in this class are excreted in human milk and because of the potential for serious adverse
reactions from cinoxacin in nursing infants, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use—The safety and effectiveness of cinoxacin in pediatric patients
and adolescents less than 18 years of age have not been established.
Cinoxacin causes arthropathy in juvenile animals (see Warnings).
Geriatric Use--Following a single 500 mg dose of cinoxacin,
peak serum concentrations in geriatric patients were similar to
those in all adults. With repeated administration of cinoxacin, no
accumulation of drug was found in the twenty patients ages 70-
89 (see Geriatric under Clinical Pharmacology). No dosage
adjustment is required based on age alone. In geriatric patients
with reduced renal function, the dosage should be reduced (see
Impaired Renal Function under Dosage and Administration).
Clinical studies of cinoxacin did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical
experience has not identified differences in responses between
the elderly and younger patients. In general, dose selection for
an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal or cardiac function, and of concomitant
disease or other drug therapy.
ADVERSE REACTIONS
In clinical studies involving 1,118 patients, the following adverse effects were considered to be
related to cinoxacin therapy:
Gastrointestinal--Nausea was reported most commonly and occurred in less than 3 in 100
patients. Other side effects, occurring less frequently (1 in 100), were anorexia, vomiting,
abdominal cramps/pain, perverse taste, and diarrhea.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Cinobac® (Cinoxacin, USP)
7
Central Nervous System--The most frequent side effects were headache and dizziness,
reported by 1 in 100 patients. Other adverse reactions possibly related to Cinobac include
insomnia, drowsiness, tingling sensation, perineal burning, photophobia, and tinnitus. These
were reported by less than 1 in 100 patients.
Hypersensitivity--Rash, urticaria, pruritus, edema, angioedema, and eosinophilia were
reported by less than 3 in 100 patients. Rare cases of anaphylactic reactions have been reported.
Toxic epidermal necrolysis has been reported very rarely. Erythema multiforme and Stevens-
Johnson syndrome have been reported with cinoxacin and other drugs in this class.
Hematologic--Rare reports of thrombocytopenia.
Laboratory values reported to be abnormal were, in descending order of frequency, elevation
of BUN (1 in 100), AST (SGOT), ALT (SGPT), serum creatinine, and alkaline phosphatase;
and reduction in hematocrit/hemoglobin (each less than 1 in 100).
Although not observed in the 1,118 patients treated with cinoxacin, the following side effects
have been reported for other drugs in the same pharmacologically active and chemically related
class: restlessness, nervousness, change in color perception, difficulty in focusing, decrease in
visual acuity, double vision, weakness, constipation, erythema and bullae, feelings of
disorientation or agitation or acute anxiety, palpitation, soreness of the gums, joint stiffness,
swelling of the extremities, and toxic psychosis or convulsions (rare). All adverse reactions
observed with drugs in this class were reversible.
The most frequently reported adverse events in postmarketing surveillance of cinoxacin have
been rash and anaphylactic reactions. Other frequently reported reactions have been pruritus,
urticaria, allergic reactions, nausea, abdominal pain, and headache.
OVERDOSAGE
Signs and Symptoms--Symptoms following an overdose of cinoxacin may include anorexia,
nausea, vomiting, epigastric distress, and diarrhea. The severity of the epigastric distress and the
diarrhea are dose related. Headache, dizziness, insomnia, photophobia, tinnitus, and a tingling
sensation have been reported in some patients. If other symptoms are present, they are probably
secondary to an underlying disease state, an allergic reaction, or the ingestion of a second
medication with toxicity.
Treatment--In all cases of suspected overdosage, call your regional Poison Control Center to
obtain the most up-to-date information about the treatment of overdose. This recommendation is
made because, in general, information regarding the treatment of overdosage may change more
rapidly than do package inserts.
In managing overdosage, consider the possibility of multiple drug overdoses, interaction among
drugs, and unusual drug kinetics in your patient.
Patients who have ingested an overdose of cinoxacin should be kept well hydrated to prevent
crystalluria.
Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and
maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc.
Absorption of drugs from the gastrointestinal tract may be decreased by giving activated
charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal
instead of, or in addition to, gastric emptying. Repeated doses of charcoal over time may hasten
elimination of some drugs that have been absorbed. Safeguard the patient's airway when
employing gastric emptying or charcoal.
Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been
established as beneficial for an overdose of cinoxacin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cinobac® (Cinoxacin, USP)
8
DOSAGE AND ADMINISTRATION
The usual adult dosage for the treatment of urinary tract infections is 1 g daily, administered
orally in 2 or 4 divided doses (500 mg b.i.d. or 250 mg q.i.d. respectively) for 7 to 14 days.
Doses should be administered at least 2 hours before or 2 hours
after antacids containing magnesium or aluminum, as well as
sucralfate, metal cations such as iron, and multivitamin
preparations with zinc or Videx (didanosine) chewable tablets or
the pediatric powder for oral solution. Although susceptible organisms may
be eradicated within a few days after therapy has begun, the full treatment course is
recommended.
Impaired Renal Function--When renal function is impaired, a reduced dosage must be
employed. After an initial dose of 500 mg, a maintenance dosage schedule should be used (see
table).
MAINTENANCE DOSAGE GUIDE
FOR PATIENTS WITH RENAL IMPAIRMENT
Creatinine
Renal
Clearance
Function
Dosage
mL/min/1.73 m2
>80
Normal
500 mg
b.i.d.
80-50
Mild
250 mg
Impairment
t.i.d.
50-20
Moderate
250 mg
Impairment
b.i.d.
<20
Marked
250 mg
Impairment
q.d.
Administration of Cinobac to anuric patients is not recommended.
When only serum creatinine is available, the following formula (based on sex, weight, and age
of patient) may be used to convert this value into creatinine clearance.
The serum creatinine should represent a steady state of renal function.
Males:
Weight (kg) x (140 – age)
72 x serum creatinine
Females:
0.9 x male value
Preventive Therapy--A single dose of 250 mg at bedtime for up to 5 months has been shown to
be effective in women with a history of recurrent urinary tract infections.
HOW SUPPLIED
Capsules:
250 mg, orange and green, imprinted with "OCL 55" on the cap and "CINOBAC 250 mg" on
the body, (UC 5355)--(40s) NDC 55515-055-02
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cinobac® (Cinoxacin, USP)
9
500 mg, orange and green, imprinted with "OCL 56" on the cap and "CINOBAC 500 mg" on
the body, (UC 5356)--(50s) NDC 55515-056-04
Store at controlled room temperature, 59° to 86°F (15° to 30°C).
ANIMAL PHARMACOLOGY
Crystalluria, sometimes associated with secondary urinary tract pathology, occurs in laboratory
animals treated orally with cinoxacin. In the rhesus monkey, crystalluria (without urinary tract
pathology) has been noted at doses as low as 50 mg/kg/day (lowest dose tested). Cinoxacin-
related crystalluria has not been observed in humans receiving twice the recommended daily
dosage.
Cinoxacin and other quinolones have been shown to cause arthropathy in immature animals of
most species tested (see Warnings).
Some drugs of this class have been shown to have oculotoxic potential. Cinoxacin administered
to cats at high dosages (200 mg/kg/day) resulted in retinal degeneration and other ocular changes.
The dog appeared to be somewhat resistant to these effects, but high dosages (500 mg/kg/day)
resulted in mild retinal atrophy. No cinoxacin-related ocular changes were noted in rabbit, rat,
monkey, or human studies. (In one of the studies involving the monkey, cinoxacin was
administered for 1 year at 10 times the recommended clinical dose.)
REFERENCES
1.
National Committee for Clinical Laboratory Standards, Performance standards for
antimicrobial disk susceptibility tests--5th ed. Approved Standard NCCLS Document M2-
A5, Vol 13, No 24, NCCLS, Villanova, PA, 1993.
2.
National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial
susceptibility tests for bacteria that grow aerobically--3rd ed. Approved Standard NCCLS
Document M7-A3, Vol 13, No 25, NCCLS, Villanova, PA, 1993.
Videx is a registered trademark of Bristol-Myers Squibb Company
Literature revised June 23, 1999
Mfd. for
O c l a s s e n
PHARMACEUTICALS, INC.
A Division of Watson Labs, Inc.
Corona, CA 91720
by Eli Lilly and Company
Indianapolis, IN 46285, USA
PV 1354-A UCP
PRINTED IN USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Renata Albrecht
8/1/02 05:58:33 PM
NDA 18-067/S029
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18067s29lbl.pdf', 'application_number': 18067, 'submission_type': 'SUPPL ', 'submission_number': 29}
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CORGARD® TABLETS
Nadolol Tablets USP
Rx Only
DESCRIPTION
CORGARD (nadolol) is a synthetic nonselective beta-adrenergic receptor blocking agent
designated chemically as 1-(tert-butylamino)-3-[(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-1-
naphthyl)oxy]-2-propanol. Structural formula:
C17H27NO4 MW 309.40
Nadolol is a white crystalline powder. It is freely soluble in ethanol, soluble in hydrochloric
acid, slightly soluble in water and in chloroform, and very slightly soluble in sodium
hydroxide.
CORGARD (nadolol) is available for oral administration as 20 mg, 40 mg, and 80 mg
tablets. Inactive ingredients: microcrystalline cellulose, colorant (FD&C Blue No. 2), corn
starch, magnesium stearate, povidone (except 20 mg and 40 mg), and other ingredients.
CLINICAL PHARMACOLOGY
CORGARD (nadolol) is a nonselective beta-adrenergic receptor blocking agent. Clinical
pharmacology studies have demonstrated beta-blocking activity by showing (1) reduction in
heart rate and cardiac output at rest and on exercise, (2) reduction of systolic and diastolic
blood pressure at rest and on exercise, (3) inhibition of isoproterenol-induced tachycardia,
and (4) reduction of reflex orthostatic tachycardia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CORGARD (nadolol) specifically competes with beta-adrenergic receptor agonists for
available beta receptor sites; it inhibits both the beta1 receptors located chiefly in cardiac
muscle and the beta2 receptors located chiefly in the bronchial and vascular musculature,
inhibiting the chronotropic, inotropic, and vasodilator responses to beta-adrenergic
stimulation proportionately. CORGARD has no intrinsic sympathomimetic activity and,
unlike some other beta-adrenergic blocking agents, nadolol has little direct myocardial
depressant activity and does not have an anesthetic-like membrane- stabilizing action.
Animal and human studies show that CORGARD slows the sinus rate and depresses AV
conduction. In dogs, only minimal amounts of nadolol were detected in the brain relative to
amounts in blood and other organs and tissues. CORGARD has low lipophilicity as
determined by octanol/water partition coefficient, a characteristic of certain beta-blocking
agents that has been correlated with the limited extent to which these agents cross the
blood-brain barrier, their low concentration in the brain, and low incidence of CNS-related
side effects.
In controlled clinical studies, CORGARD (nadolol) at doses of 40 to 320 mg/day has been
shown to decrease both standing and supine blood pressure, the effect persisting for
approximately 24 hours after dosing.
The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents
has not been established; however, factors that may be involved include (1) competitive
antagonism of catecholamines at peripheral (non-CNS) adrenergic neuron sites (especially
cardiac) leading to decreased cardiac output, (2) a central effect leading to reduced tonic-
sympathetic nerve outflow to the periphery, and (3) suppression of renin secretion by
blockade of the beta-adrenergic receptors responsible for renin release from the kidneys.
While cardiac output and arterial pressure are reduced by nadolol therapy, renal
hemodynamics are stable, with preservation of renal blood flow and glomerular filtration
rate.
By blocking catecholamine-induced increases in heart rate, velocity and extent of
myocardial contraction, and blood pressure, CORGARD (nadolol) generally reduces the
oxygen requirements of the heart at any given level of effort, making it useful for many
patients in the long-term management of angina pectoris. On the other hand, nadolol can
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
increase oxygen requirements by increasing left ventricular fiber length and end diastolic
pressure, particularly in patients with heart failure.
Although beta-adrenergic receptor blockade is useful in treatment of angina and
hypertension, there are also situations in which sympathetic stimulation is vital. For
example, in patients with severely damaged hearts, adequate ventricular function may
depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by
preventing the necessary facilitating effects of sympathetic activity on conduction. Beta2-
adrenergic blockade results in passive bronchial constriction by interfering with endogenous
adrenergic bronchodilator activity in patients subject to bronchospasm and may also
interfere with exogenous bronchodilators in such patients.
Absorption of nadolol after oral dosing is variable, averaging about 30 percent. Peak serum
concentrations of nadolol usually occur in three to four hours after oral administration and
the presence of food in the gastrointestinal tract does not affect the rate or extent of nadolol
absorption. Approximately 30 percent of the nadolol present in serum is reversibly bound to
plasma protein.
Unlike many other beta-adrenergic blocking agents, nadolol is not metabolized by the liver
and is excreted unchanged, principally by the kidneys.
The half-life of therapeutic doses of nadolol is about 20 to 24 hours, permitting once-daily
dosage. Because nadolol is excreted predominantly in the urine, its half-life increases in
renal failure (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Steady-state
serum concentrations of nadolol are attained in six to nine days with once-daily dosage in
persons with normal renal function. Because of variable absorption and different individual
responsiveness, the proper dosage must be determined by titration.
Exacerbation of angina and, in some cases, myocardial infarction and ventricular
dysrhythmias have been reported after abrupt discontinuation of therapy with beta-
adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of
these agents in patients without coronary artery disease has resulted in transient
symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several
mechanisms have been proposed to explain these phenomena, among them increased
sensitivity to catecholamines because of increased numbers of beta receptors.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
Angina Pectoris
CORGARD (nadolol) is indicated for the long-term management of patients with angina
pectoris.
Hypertension
CORGARD (nadolol) is indicated in the management of hypertension; it may be used alone
or in combination with other antihypertensive agents, especially thiazide-type diuretics.
CONTRAINDICATIONS
Nadolol is contraindicated in bronchial asthma, sinus bradycardia and greater than first
degree conduction block, cardiogenic shock, and overt cardiac failure (see WARNINGS).
WARNINGS
Cardiac Failure
Sympathetic stimulation may be a vital component supporting circulatory function in
patients with congestive heart failure, and its inhibition by beta-blockade may precipitate
more severe failure. Although beta-blockers should be avoided in overt congestive heart
failure, if necessary, they can be used with caution in patients with a history of failure who
are well-compensated, usually with digitalis and diuretics. Beta-adrenergic blocking agents
do not abolish the inotropic action of digitalis on heart muscle.
IN PATIENTS WITHOUT A HISTORY OF HEART FAILURE, continued use of beta-
blockers can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom
of heart failure, the patient should be digitalized and/or treated with diuretics, and the
response observed closely, or nadolol should be discontinued (gradually, if possible).
Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal—Hypersensitivity to
catecholamines has been observed in patients withdrawn from beta-blocker therapy;
exacerbation of angina and, in some cases, myocardial infarction have occurred after
abrupt discontinuation of such therapy. When discontinuing chronically administered
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For current labeling information, please visit https://www.fda.gov/drugsatfda
nadolol, particularly in patients with ischemic heart disease, the dosage should be gradually
reduced over a period of one to two weeks and the patient should be carefully monitored. If
angina markedly worsens or acute coronary insufficiency develops, nadolol administration
should be reinstituted promptly, at least temporarily, and other measures appropriate for the
management of unstable angina should be taken. Patients should be warned against
interruption or discontinuation of therapy without the physician's advice. Because coronary
artery disease is common and may be unrecognized, it may be prudent not to discontinue
nadolol therapy abruptly even in patients treated only for hypertension.
Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema)
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE
BETA-BLOCKERS. Nadolol should be administered with caution since it may block
bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2
receptors.
Major Surgery
Because beta-blockade impairs the ability of the heart to respond to reflex stimuli and may
increase the risks of general anesthesia and surgical procedures, resulting in protracted
hypotension or low cardiac output, it has generally been suggested that such therapy
should be withdrawn several days prior to surgery. Recognition of the increased sensitivity
to catecholamines of patients recently withdrawn from beta-blocker therapy, however, has
made this recommendation controversial. If possible, beta-blockers should be withdrawn
well before surgery takes place. In the event of emergency surgery, the anesthesiologist
should be informed that the patient is on beta-blocker therapy. The effects of nadolol can be
reversed by administration of beta-receptor agonists such as isoproterenol, dopamine,
dobutamine, or levarterenol. Difficulty in restarting and maintaining the heart beat has also
been reported with beta-adrenergic receptor blocking agents.
Diabetes and Hypoglycemia
Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms
(e.g., tachycardia and blood pressure changes) of acute hypoglycemia. This is especially
important with labile diabetics. Beta-blockade also reduces the release of insulin in
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For current labeling information, please visit https://www.fda.gov/drugsatfda
response to hyperglycemia; therefore, it may be necessary to adjust the dose of antidiabetic
drugs.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of
hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed
carefully to avoid abrupt withdrawal of beta-adrenergic blockade which might precipitate a
thyroid storm.
PRECAUTIONS
Impaired Renal Function
Nadolol should be used with caution in patients with impaired renal function (see DOSAGE
AND ADMINISTRATION).
Information for Patients
Patients, especially those with evidence of coronary artery insufficiency, should be warned
against interruption or discontinuation of nadolol therapy without the physician's advice.
Although cardiac failure rarely occurs in properly selected patients, patients being treated
with beta-adrenergic blocking agents should be advised to consult the physician at the first
sign or symptom of impending failure. The patient should also be advised of a proper
course in the event of an inadvertently missed dose.
Drug Interactions
When administered concurrently, the following drugs may interact with beta-adrenergic
receptor blocking agents:
Anesthetics, general—exaggeration of the hypotension induced by general anesthetics (see
WARNINGS, Major Surgery).
Antidiabetic drugs (oral agents and insulin)—hypoglycemia or hyperglycemia; adjust
dosage of antidiabetic drug accordingly (see WARNINGS, Diabetes and Hypoglycemia).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Catecholamine-depleting drugs (e.g., reserpine)—additive effect; monitor closely for
evidence of hypotension and/or excessive bradycardia (e.g., vertigo, syncope, postural
hypotension).
Digitalis glycosides—Both digitalis glycosides and beta-blockers slow atrioventricular
conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Response to Treatment for Anaphylactic Reaction—While taking beta-blockers, patients
with a history of severe anaphylactic reaction to a variety of allergens may be more reactive
to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be
unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In chronic oral toxicologic studies (one to two years) in mice, rats, and dogs, nadolol did not
produce any significant toxic effects. In two-year oral carcinogenic studies in rats and mice,
nadolol did not produce any neoplastic, preneoplastic, or non-neoplastic pathologic lesions.
In fertility and general reproductive performance studies in rats, nadolol caused no adverse
effects.
Pregnancy
Category C
In animal reproduction studies with nadolol, evidence of embryo- and fetotoxicity was found
in rabbits, but not in rats or hamsters, at doses 5 to 10 times greater (on a mg/kg basis)
than the maximum indicated human dose. No teratogenic potential was observed in any of
these species.
There are no adequate and well-controlled studies in pregnant women. Nadolol should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia,
hypoglycemia, and associated symptoms.
Nursing Mothers
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Nadolol is excreted in human milk. Because of the potential for adverse effects in nursing
infants, a decision should be made whether to discontinue nursing or to discontinue therapy
taking into account the importance of CORGARD (nadolol) to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Most adverse effects have been mild and transient and have rarely required withdrawal of
therapy.
Cardiovascular
Bradycardia with heart rates of less than 60 beats per minute occurs commonly, and heart
rates below 40 beats per minute and/or symptomatic bradycardia were seen in about 2 of
100 patients. Symptoms of peripheral vascular insufficiency, usually of the Raynaud type,
have occurred in approximately 2 of 100 patients. Cardiac failure, hypotension, and
rhythm/conduction disturbances have each occurred in about 1 of 100 patients. Single
instances of first degree and third degree heart block have been reported; intensification of
AV block is a known effect of beta-blockers (see also CONTRAINDICATIONS,
WARNINGS, and PRECAUTIONS).
Central Nervous System
Dizziness or fatigue has been reported in approximately 2 of 100 patients; paresthesias,
sedation, and change in behavior have each been reported in approximately 6 of 1000
patients.
Respiratory
Bronchospasm has been reported in approximately 1 of 1000 patients (see
CONTRAINDICATIONS and WARNINGS).
Gastrointestinal
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Nausea, diarrhea, abdominal discomfort, constipation, vomiting, indigestion, anorexia,
bloating, and flatulence have been reported in 1 to 5 of 1000 patients.
Miscellaneous
Each of the following has been reported in 1 to 5 of 1000 patients: rash; pruritus; headache;
dry mouth, eyes, or skin; impotence or decreased libido; facial swelling; weight gain; slurred
speech; cough; nasal stuffiness; sweating; tinnitus; blurred vision. Reversible alopecia has
been reported infrequently.
The following adverse reactions have been reported in patients taking nadolol and/or other
beta-adrenergic blocking agents, but no causal relationship to nadolol has been
established.
Central Nervous System
Reversible mental depression progressing to catatonia; visual disturbances; hallucinations;
an acute reversible syndrome characterized by disorientation for time and place, short-term
memory loss, emotional lability with slightly clouded sensorium, and decreased
performance on neuropsychometrics.
Gastrointestinal
Mesenteric arterial thrombosis; ischemic colitis; elevated liver enzymes.
Hematologic
Agranulocytosis; thrombocytopenic or nonthrombocytopenic purpura.
Allergic
Fever combined with aching and sore throat; laryngospasm; respiratory distress.
Miscellaneous
Pemphigoid rash; hypertensive reaction in patients with pheochromocytoma; sleep
disturbances; Peyronie's disease.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not
been reported with nadolol.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Nadolol can be removed from the general circulation by hemodialysis.
In addition to gastric lavage, the following measures should be employed, as appropriate. In
determining the duration of corrective therapy, note must be taken of the long duration of
the effect of nadolol.
Excessive Bradycardia
Administer atropine (0.25 to 1.0 mg). If there is no response to vagal blockade, administer
isoproterenol cautiously.
Cardiac Failure
Administer a digitalis glycoside and diuretic. It has been reported that glucagon may also be
useful in this situation.
Hypotension
Administer vasopressors, e.g., epinephrine or levarterenol. (There is evidence that
epinephrine may be the drug of choice.)
Bronchospasm
Administer a beta2-stimulating agent and/or a theophylline derivative.
DOSAGE AND ADMINISTRATION
DOSAGE MUST BE INDIVIDUALIZED. CORGARD (NADOLOL) MAY BE ADMINISTERED
WITHOUT REGARD TO MEALS.
Angina Pectoris
The usual initial dose is 40 mg CORGARD (nadolol) once daily. Dosage may be gradually
increased in 40 to 80 mg increments at 3 to 7 day intervals until optimum clinical response
is obtained or there is pronounced slowing of the heart rate. The usual maintenance dose is
40 or 80 mg administered once daily. Doses up to 160 or 240 mg administered once daily
may be needed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The usefulness and safety in angina pectoris of dosage exceeding 240 mg per day have
not been established. If treatment is to be discontinued, reduce the dosage gradually over a
period of one to two weeks (see WARNINGS).
Hypertension
The usual initial dose is 40 mg CORGARD (nadolol) once daily, whether it is used alone or
in addition to diuretic therapy. Dosage may be gradually increased in 40 to 80 mg
increments until optimum blood pressure reduction is achieved. The usual maintenance
dose is 40 or 80 mg administered once daily. Doses up to 240 or 320 mg administered
once daily may be needed.
Dosage Adjustment in Renal Failure
Absorbed nadolol is excreted principally by the kidneys and, although nonrenal elimination
does occur, dosage adjustments are necessary in patients with renal impairment. The
following dose intervals are recommended:
Creatinine Clearance
(mL/min/1.73m2)
Dosage Interval
(hours)
>50
24
31–50
24–36
10–30
24–48
<10
40–60
HOW SUPPLIED
CORGARD Tablets (Nadolol Tablets USP)
20 mg tablets in bottles of 100 (NDC 60793–800–01), 40 mg tablets in bottles of 100 (NDC
60793–801–01) and 80 mg tablets in bottles of 100 (NDC 60793–802–01).
All tablets are scored (bisect bar) and easy to break. Tablet identification numbers: 20 mg,
232; 40 mg, 207; and 80 mg, 241.
STORAGE
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Store at room temperature; avoid excessive heat. Protect from light. Keep bottle tightly
closed.
Prescribing Information as of July 2007.
Manufactured and Distributed by: King Pharmaceuticals, Inc., Bristol, TN 37620
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:32.352629
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018063s060lbl.pdf', 'application_number': 18063, 'submission_type': 'SUPPL ', 'submission_number': 60}
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NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 3 of 48
FULL PRESCRIBING INFORMATION
BOXED WARNING
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. Children under the age of two
years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple
anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by
mental retardation, and those with organic brain disease. When Depakene products are used in this patient
group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed
against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and
vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored
closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at
frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida).
Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the
management of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective
contraception while using valproate. [see Warnings and Precautions (5.2), 5.3].
A Medication Guide describing the risks of valproate is available for patients. [see Patient Counseling
Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases
Reference ID: 3026475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 4 of 48
have been reported shortly after initial use as well as after several years of use. Patients and guardians should be
warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require
prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative
treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and
Precautions (5.4)].
1 INDICATIONS AND USAGE
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of patients with
complex partial seizures that occur either in isolation or in association with other types of seizures. Depakene
(valproic acid) is indicated for use as sole and adjunctive therapy in the treatment of simple and complex
absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by
certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term
used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole without chewing
to avoid local irritation of the mouth and throat.
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it should be taken as
soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double
the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and
pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakene
dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide,
phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 5 of 48
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15
mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.
Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not they are in the
usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate
for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations
above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher
doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week
to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No
recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.
This reduction may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a
concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this period for
increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be
increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma
levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50
to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day
can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either
carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of carbamazepine or phenytoin
dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 6 of 48
concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of
concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until
seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60
mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.
However, therapeutic valproate serum concentration for most patients with absence seizures is considered to
range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations
[see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to
prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant
hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15 mg/kg/day):
Table 1: Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the
elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and
with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.
Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 7 of 48
intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the
basis of both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-
related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations
of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of
improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence
of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly
building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing
the trademark Depakene for product identification, in bottles of 100 capsules and as a red Oral Solution
containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
Depakene should not be administered to patients with hepatic disease or significant hepatic dysfunction [see
Warnings and Precautions (5.1)].
Depakene is contraindicated in patients with known hypersensitivity to the drug [see Warnings and
Precautions (5.11)].
Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions
(5.5)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have
occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non
specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
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epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter,
especially during the first six months. However, healthcare providers should not rely totally on serum
biochemistry since these tests may not be abnormal in all instances, but should also consider the results of
careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior history of hepatic
disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with
severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at
particular risk. Experience has indicated that children under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When
Depakene products are used in this patient group, they should be used with extreme caution and as a sole
agent. The benefits of therapy should be weighed against the risks. Above this age group, experience has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or
apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed
Warning and Contraindications (4)].
5.2 Use in Women of Childbearing Potential
Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may
occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential
unless the drug is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
migraine). Women should use effective contraception while using valproate. Women who are planning a
pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy,
and alternative therapeutic options should be considered for these patients. [see Boxed Warning and Use in
Specific Populations (8.1)].
To prevent major seizures, Depakene should not be discontinued abruptly, as this can precipitate status
epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
pregnancy decreases the risk for congenital neural tube defects in the general population.
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5.3 Birth Defects and Neurobehavioral Adverse Effects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that
maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial
defects, cardiovascular malformations and malformations involving various body systems). The rate of
congenital malformations among babies born to mothers using valproate is about four times higher than the
rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that
folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk
for congenital neural tube defects in the general population.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
States and United Kingdom that found that children with prenatal exposure to valproate had lower
Differential Ability Scale (D.A.S) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal
exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98
104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which
has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years.
The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo
IQ testing and generally correlates with IQ scores later in childhood.
Although all of the available studies have methodological limitations, the weight of the evidence supports
the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development.
In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and
demonstrated behavioral deficits. [see Use in Specific Populations (8.1)]
5.4 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some
cases have occurred shortly after initial use as well as after several years of use. The rate based upon the
reported cases exceeds that expected in the general population and there have been cases in which pancreatitis
recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without
alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians
should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.
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Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see
Boxed Warning].
5.5 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate
therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly
ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should
be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma,
encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained
mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and
lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of
UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or
symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while
receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy)
and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and
Precautions (5.9)].
5.6 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored
for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in
mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after
starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials
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included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24
weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications
suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5
100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
Drug Patients
Relative Risk: Incidence of Events in
Risk Difference:
with Events Per
with Events Per
Drug Patients/Incidence in Placebo
Additional Drug
1000 Patients
1000 Patients
Patients
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical
trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and
psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed
are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and
behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider
whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
5.7 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-
related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients with epilepsy, 34/126
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patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x
109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to
normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the
probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110
mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses
should therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving
Depakene (valproic acid) be monitored for platelet count and coagulation parameters prior to planned surgery.
Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the
dosage or withdrawal of therapy.
5.8 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal
liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status,
hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and
Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate
interventions for treatment of hyperammonemia should be initiated, and such patients should undergo
investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions
(5.5, 5.8, 5.9)].
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of
plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or
without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of
hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive
function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see
Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either
drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate
monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced
hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without
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encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing
defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy,
vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)].
5.10 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in
association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This
adverse reaction can also occur in patients using concomitant topiramate with valproate after starting
topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)].
Consideration should be given to stopping valproate in patients who develop hypothermia, which may be
manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant
alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical
management and assessment should include examination of blood ammonia levels.
5.11 Multi-organ Hypersensitivity Reaction
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation
of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days).
Although there have been a limited number of reports, many of these cases resulted in hospitalization and at
least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients
typically, although not exclusively, presented with fever and rash associated with other organ system
involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test
abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus,
nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected,
valproate should be discontinued and an alternative treatment started. Although the existence of cross
sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated
with multi-organ hypersensitivity would indicate this to be a possibility.
5.12 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may
reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum
valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative
antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop
significantly or seizure control deteriorates [see Drug Interactions (7.1)].
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5.13 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses
were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate
patients had somnolence compared to placebo, and although not statistically significant, there was a higher
proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than
with placebo. In some patients with somnolence (approximately one-half), there was associated reduced
nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients,
dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should
be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see
Dosage and Administration (2.2)].
5.14 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme induction,
periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the
early course of therapy [see Drug Interactions (7)].
5.15 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of
the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of
these is unknown.
5.16 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under
certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of
these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy.
Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the
viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
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6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may
not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium) tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote
was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was
the primary reason for discontinuation in the Depakote -treated patients (6%), compared to 1% of placebo-
treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote -treated patients
and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive
therapy for the treatment of complex partial seizures. Since patients were also treated with other antiepilepsy
drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to
Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive
Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
Placebo (%)
(n = 77)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
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Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose
Depakote group, and for which the incidence was greater than in the low dose group, in a controlled trial of
Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another
antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the
following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other
antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Depakote Monotherapy
for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
Low Dose (%)
(n = 131)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
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Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater
incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358
patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal
dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
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6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic episodes
associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more
of patients from two placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine
headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two
placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous
reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea, vomiting,
and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea,
abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased
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appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium
may result in reduction of gastrointestinal side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic
medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis,
"spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and Parkinsonism
have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate
alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has
developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following drug
withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in
patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case
in a 6 month old infant taking valproate and several other concomitant medications. An additional case of
toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several
concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have
been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be
reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage
[see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis,
hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency,
bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be
dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes
in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and
Precautions (5.1)].
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Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not
been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.4)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and inappropriate ADH
secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent
nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of
women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of
glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine,
and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will
generally have longer half-lives and higher concentrations than patients receiving polytherapy with
antiepilepsy drugs.
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In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to
have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a
relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations
should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed
medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions
are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to
pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate.
Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β
oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was
decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin.
Caution should be observed if valproate and aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving
carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may
result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid
concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or
anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure
control deteriorates [see Warnings and Precautions (5.12)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy
(n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL)
compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak
concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when
felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily
dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage
adjustment may be necessary when it is co-administered with rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox,
Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients
already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already
receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on
the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not
exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
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Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females)
who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a
34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate
and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate
and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be
considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E)
increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a history of
absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co
administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy
volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and
20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged
upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg
with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in
elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide
alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be
monitored for alterations in serum concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from
26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced
when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic
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epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See
lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID
for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30%
decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose
excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate
serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for
neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate
dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co
administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was
associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume
of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent
volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of
valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added
to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is
unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic
relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted
in patients taking anticoagulants.
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Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by
38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently
administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with
clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers
(n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers
(n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on
valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and
without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)].
Concomitant administration of topiramate with valproate has also been associated with hypothermia in
patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients
in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)].
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should encourage pregnant
patients taking Depakene to enroll in the NAAED Pregnancy Registry. This can be done by calling toll free 1
888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at
the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other
adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication
increases the risk of congenital malformations, particularly neural tube defects, but also malformations
involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major
structural abnormalities is greatest during the first trimester; however, other serious developmental effects
can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born
to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than
the rate among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. [see Warnings and Precautions (5.3)].
In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated
behavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal valproate
use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%,
compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in
10,000 births).
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• To prevent major seizures, women with epilepsy should not discontinue Depakene abruptly, as this can
precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor
seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the
drug may be considered prior to and during pregnancy in individual cases if the seizure disorder
severity and frequency do not pose a serious threat to the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered to
pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
pregnancy decreases the risk for congenital neural tube defects in the general population. It is not
known whether the risk of neural tube defects in the offspring of women receiving valproate is
reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception
and during pregnancy should be routinely recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A
patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth
to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in
pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also
been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of
neural tube defects and other structural abnormalities. Based on published data from the CDC’s National
Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%.
The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to
2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal
valproate exposure were reported among offspring of 149 enrolled women who used valproate during
pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial
defects, cardiovascular malformations and malformations of varying severity involving other body systems.
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The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% – 16.9%)
in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during
pregnancy (dose range 500 – 2000 mg/day). The major malformation rate among the internal comparison
group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy
was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following
exposure in utero to any other antiepileptic drug monotherapy.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
States and United Kingdom that found that children with prenatal exposure to valproate had lower
Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98
104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94-104]). The D.A.S., which has
a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The
D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ
testing and generally correlates with IQ scores later in childhood.
Although all of the available studies have methodological limitations, the weight of the evidence supports a
causal association between valproate exposure in utero and subsequent adverse effects on cognitive
development.
There are published case reports of fatal hepatic failure in offspring of women who used valproate during
pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal
structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment
of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body
surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac,
and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been
reported following valproate administration during critical periods of organogenesis, and the teratogenic
response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor,
and social interaction deficits) and brain histopathological changes have also been reported in mice and rat
offspring exposed prenatally to clinically relevant doses of valproate.
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8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing
woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk
of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning].
When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to
attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and
10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of
10 years, children have pharmacokinetic parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid
concentrations. Interpretation of valproic acid concentrations in children should include consideration of
factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication
of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric
patients were shown to be comparable to those in adults [see Adverse Reactions (6)].
Nonclinical Developmental Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal
dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated
during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was
less than the maximum recommended human dose on a mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania
associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65
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years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain,
somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether
these events indicate additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for
somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and
dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage
and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been
reported; however, patients have recovered from valproate levels as high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem
hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or
emesis will vary with the time since ingestion. General supportive measures should be applied with particular
attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone
could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients
with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also known as
dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic
odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule contains 250
mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben,
and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and
natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate
exerts its antiepileptic effects have not been established. It has been suggested that its activity in epilepsy is
related to increased brain concentrations of gamma-aminobutyric acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented. One
contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the
clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the
bioactive valproate species.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 32 of 48
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free
fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate, although some
patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules
deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may
vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or
postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food
or the capsule is taken intact), these differences should be of minor clinical importance under the steady state
conditions achieved in chronic use in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax could be
important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater
influence on the rate of absorption of the Depakote tablet (increase in Tmax from 4 to 8 hours) than on the
absorption of the Depakote sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with
dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be
affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in
primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability
(extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma
peak to trough concentrations between valproate formulations are inconsequential from a practical clinical
standpoint.
Co-administration of oral valproate products with food and substitution among the various Depakote and
Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see
Dosage and Administration (2.1)]. Nonetheless, any changes in dosage administration, or the addition or
discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status
and valproate plasma concentrations.
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FDA Approved Labeling Text dated October 7, 2011
Page 33 of 48
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction increases from
approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the
elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of
other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin,
carbamazepine, warfarin, and tolbutamide). (See Drug Interactions (7.2) for more detailed information on the
pharmacokinetic interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about
10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an
administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major
metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is
eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in
urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase
proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding.
The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2,
respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92
L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing
regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing
enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine,
phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate
Reference ID: 3026475
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FDA Approved Labeling Text dated October 7, 2011
Page 34 of 48
clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant
antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate valproate compared
to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of
glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased
volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-
life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children
greater than 2 months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e.,
mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that
approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be
reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free
fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and
Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and females (4.8
± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
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Page 35 of 48
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.3)]. Liver disease impairs the
capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7
patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that
study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with
decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate.
Accordingly, monitoring of total concentrations may be misleading since free concentrations may be
substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure
(creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by
about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein
binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum
recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the
incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend
for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for
humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects
in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats.
Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children
taking valproate, but this association was not observed in another study conducted in adults. There is some
evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an
increase in SCE frequency is not known.
Fertility
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Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately
equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150
mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility
studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately
equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on
sperm production and fertility in humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur in isolation or
in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients
who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses
of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range"
were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo.
Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.
Table 5: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex
partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A
positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative
percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is
shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any
particular level of improvement was consistently higher for Depakote than for placebo. For example, 45% of
patients treated with Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of
patients treated with placebo.
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Page 37 of 48 Graphic of percent of patients on X axis, reduction in CPS rate on Y access
The second study assessed the capacity of Depakote to reduce the incidence of CPS when administered as the
sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose
treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they
continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with
adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized phase were then
brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an
interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In
patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy
were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-randomization
assessment.
Table 6: Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex
partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive
percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent
reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is
shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients
achieving any particular level of reduction was consistently higher for high dose Depakote than for low dose
Depakote. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a reduction in
complex partial seizure rates compared to 54% of patients receiving low dose Depakote. % of patients on X access, percent reduction in CPS rate on Y access
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing
the trademark Depakene for product identification, in bottles of 100 capsules (NDC 0074-5681-13), and as a
red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of
16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
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17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly
[see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and
Precautions (5.4)].
17.3 Birth Defects and Neurobehavioral Development Adverse Effects
Prescribers should inform pregnant women and women of childbearing potential that use of Depakene during
pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers
should advise women to use effective contraception while using valproate. When appropriate, prescribers
should counsel these patients about alternative therapeutic options. This is particularly important when
valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs
during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific
Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Patients, their caregivers, and families should be counseled that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal
thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the
healthcare providers [see Warnings and Precautions (5.6)].
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17.5 Hyperammonemia
Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and
be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)].
17.6 CNS depression
Since valproate products may produce CNS depression, especially when combined with another CNS
depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an
automobile or operating dangerous machinery, until it is known that they do not become drowsy from the
drug.
17.7 Multi-organ Hypersensitivity Reaction
Patients should be instructed that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see
Warnings and Precautions (5.11)].
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MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get a refill.
There may be new information. This information does not take the place of talking to your healthcare provider
about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years old.
The risk of getting this serious liver damage is more likely to happen within the first 6 months of
treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
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o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at
risk for serious birth defects. The most common birth defects with Depakote or Depakene affect
the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur
in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These
defects can begin in the first month, even before you know you are pregnant. Other birth defects
can happen.
o Birth defects may occur even in children born to women who are not taking any medicines and
do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the
chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at
risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of birth defects.
o All women of child-bearing age should talk to their healthcare provider about using other
possible treatments instead of Depakote or Depakene. If the decision is made to use
Depakote or Depakene, you should use effective birth control (contraception) unless you
are planning to become pregnant.
o Tell your healthcare provider right away if you become pregnant while taking Depakote or
Depakene. You and your healthcare provider should decide if you will continue to take Depakote
or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your
healthcare provider about registering with the North American Antiepileptic Drug Pregnancy
Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry
is to collect information about the safety of antiepileptic drugs during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a
very small number of people, about 1 in 500.
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Call a healthcare provider right away if you have any of these symptoms, especially if they are
new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or
Depakene suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has
epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or
actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
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• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or
with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in
Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and
Depakene.
• have a genetic problem called urea cycle disorder
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare
provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and non
prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each
time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider
will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
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• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew
Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can
not swallow Depakote or Depakene whole. You may need a different medicine.
• Depakote sprinkle capsules may be swallowed whole, or they may be opened and the contents may be
sprinkled on a small amount of soft food, such as applesauce or pudding. See the Patient Instructions
for Use at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle
capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control
Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other
medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your
doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may
make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affect
you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 950F, feeling tired,
confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin blistering and
peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat,
trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less
than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your
doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
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• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information, ask your
healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800
FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene to
other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Depakote or Depakene. If you
would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare
provider for information about Depakote or Depakene that is written for health professionals.
For more information, go to www.rxabbott.com or call 1-800-633-9110.
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What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline
cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide,
and triacetin. The 500 mg tablets also contain iron oxide and polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch
(contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron
oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol,
sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
500 mg is Mfd. By Abbott Laboratories, North Chicago, IL 60064 U.S.A. or
Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
For Abbott Laboratories, North Chicago, IL 60064 U.S.A.
Depakote Tablets
Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
Abbott Laboratories, North Chicago, IL 60064, U.S.A.Depakene Capsules
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Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Issued 10/2011 Abbott Laboratories
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reference ID: 3026475
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FULL PRESCRIBING INFORMATION
BOXED WARNING
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. Children under the age of two
years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple
anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by
mental retardation, and those with organic brain disease. When Depakene products are used in this patient
group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed
against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and
vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored
closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at
frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida).
Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the
management of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective
contraception while using valproate. [see Warnings and Precautions (5.2), 5.3].
A Medication Guide describing the risks of valproate is available for patients. [see Patient Counseling
Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases
Reference ID: 3026475
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have been reported shortly after initial use as well as after several years of use. Patients and guardians should be
warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require
prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative
treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and
Precautions (5.4)].
1 INDICATIONS AND USAGE
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of patients with
complex partial seizures that occur either in isolation or in association with other types of seizures. Depakene
(valproic acid) is indicated for use as sole and adjunctive therapy in the treatment of simple and complex
absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by
certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term
used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole without chewing
to avoid local irritation of the mouth and throat.
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it should be taken as
soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double
the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and
pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakene
dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide,
phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
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Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15
mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.
Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not they are in the
usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate
for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations
above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher
doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week
to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No
recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.
This reduction may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a
concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this period for
increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be
increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma
levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50
to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day
can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either
carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of carbamazepine or phenytoin
dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other
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concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of
concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until
seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60
mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.
However, therapeutic valproate serum concentration for most patients with absence seizures is considered to
range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations
[see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to
prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant
hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15 mg/kg/day):
Table 1: Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the
elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and
with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.
Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid
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intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the
basis of both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-
related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations
of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of
improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence
of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly
building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing
the trademark Depakene for product identification, in bottles of 100 capsules and as a red Oral Solution
containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
Depakene should not be administered to patients with hepatic disease or significant hepatic dysfunction [see
Warnings and Precautions (5.1)].
Depakene is contraindicated in patients with known hypersensitivity to the drug [see Warnings and
Precautions (5.11)].
Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions
(5.5)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have
occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non
specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with
Reference ID: 3026475
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epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter,
especially during the first six months. However, healthcare providers should not rely totally on serum
biochemistry since these tests may not be abnormal in all instances, but should also consider the results of
careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior history of hepatic
disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with
severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at
particular risk. Experience has indicated that children under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When
Depakene products are used in this patient group, they should be used with extreme caution and as a sole
agent. The benefits of therapy should be weighed against the risks. Above this age group, experience has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or
apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed
Warning and Contraindications (4)].
5.2 Use in Women of Childbearing Potential
Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may
occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential
unless the drug is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
migraine). Women should use effective contraception while using valproate. Women who are planning a
pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy,
and alternative therapeutic options should be considered for these patients. [see Boxed Warning and Use in
Specific Populations (8.1)].
To prevent major seizures, Depakene should not be discontinued abruptly, as this can precipitate status
epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
pregnancy decreases the risk for congenital neural tube defects in the general population.
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5.3 Birth Defects and Neurobehavioral Adverse Effects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that
maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial
defects, cardiovascular malformations and malformations involving various body systems). The rate of
congenital malformations among babies born to mothers using valproate is about four times higher than the
rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that
folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk
for congenital neural tube defects in the general population.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
States and United Kingdom that found that children with prenatal exposure to valproate had lower
Differential Ability Scale (D.A.S) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal
exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98
104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which
has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years.
The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo
IQ testing and generally correlates with IQ scores later in childhood.
Although all of the available studies have methodological limitations, the weight of the evidence supports
the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development.
In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and
demonstrated behavioral deficits. [see Use in Specific Populations (8.1)]
5.4 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some
cases have occurred shortly after initial use as well as after several years of use. The rate based upon the
reported cases exceeds that expected in the general population and there have been cases in which pancreatitis
recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without
alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians
should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.
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Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see
Boxed Warning].
5.5 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate
therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly
ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should
be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma,
encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained
mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and
lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of
UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or
symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while
receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy)
and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and
Precautions (5.9)].
5.6 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored
for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in
mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after
starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials
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included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24
weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications
suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5
100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
Drug Patients
Relative Risk: Incidence of Events in
Risk Difference:
with Events Per
with Events Per
Drug Patients/Incidence in Placebo
Additional Drug
1000 Patients
1000 Patients
Patients
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical
trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and
psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed
are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and
behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider
whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
5.7 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-
related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients with epilepsy, 34/126
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patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x
109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to
normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the
probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110
mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses
should therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving
Depakene (valproic acid) be monitored for platelet count and coagulation parameters prior to planned surgery.
Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the
dosage or withdrawal of therapy.
5.8 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal
liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status,
hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and
Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate
interventions for treatment of hyperammonemia should be initiated, and such patients should undergo
investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions
(5.5, 5.8, 5.9)].
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of
plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or
without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of
hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive
function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see
Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either
drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate
monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced
hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without
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encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing
defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy,
vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)].
5.10 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in
association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This
adverse reaction can also occur in patients using concomitant topiramate with valproate after starting
topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)].
Consideration should be given to stopping valproate in patients who develop hypothermia, which may be
manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant
alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical
management and assessment should include examination of blood ammonia levels.
5.11 Multi-organ Hypersensitivity Reaction
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation
of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days).
Although there have been a limited number of reports, many of these cases resulted in hospitalization and at
least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients
typically, although not exclusively, presented with fever and rash associated with other organ system
involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test
abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus,
nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected,
valproate should be discontinued and an alternative treatment started. Although the existence of cross
sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated
with multi-organ hypersensitivity would indicate this to be a possibility.
5.12 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may
reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum
valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative
antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop
significantly or seizure control deteriorates [see Drug Interactions (7.1)].
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5.13 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses
were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate
patients had somnolence compared to placebo, and although not statistically significant, there was a higher
proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than
with placebo. In some patients with somnolence (approximately one-half), there was associated reduced
nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients,
dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should
be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see
Dosage and Administration (2.2)].
5.14 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme induction,
periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the
early course of therapy [see Drug Interactions (7)].
5.15 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of
the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of
these is unknown.
5.16 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under
certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of
these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy.
Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the
viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
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6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may
not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium) tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote
was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was
the primary reason for discontinuation in the Depakote -treated patients (6%), compared to 1% of placebo-
treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote -treated patients
and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive
therapy for the treatment of complex partial seizures. Since patients were also treated with other antiepilepsy
drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to
Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive
Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
Placebo (%)
(n = 77)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
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Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose
Depakote group, and for which the incidence was greater than in the low dose group, in a controlled trial of
Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another
antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the
following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other
antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Depakote Monotherapy
for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
Low Dose (%)
(n = 131)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
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Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater
incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358
patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal
dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
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6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic episodes
associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more
of patients from two placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine
headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two
placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous
reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea, vomiting,
and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea,
abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased
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appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium
may result in reduction of gastrointestinal side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic
medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis,
"spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and Parkinsonism
have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate
alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has
developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following drug
withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in
patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case
in a 6 month old infant taking valproate and several other concomitant medications. An additional case of
toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several
concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have
been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be
reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage
[see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis,
hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency,
bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be
dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes
in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and
Precautions (5.1)].
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Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not
been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.4)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and inappropriate ADH
secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent
nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of
women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of
glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine,
and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will
generally have longer half-lives and higher concentrations than patients receiving polytherapy with
antiepilepsy drugs.
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In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to
have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a
relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations
should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed
medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions
are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to
pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate.
Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β
oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was
decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin.
Caution should be observed if valproate and aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving
carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may
result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid
concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or
anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure
control deteriorates [see Warnings and Precautions (5.12)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy
(n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL)
compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak
concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when
felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily
dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage
adjustment may be necessary when it is co-administered with rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox,
Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients
already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already
receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on
the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not
exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
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Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females)
who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a
34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate
and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate
and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be
considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E)
increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a history of
absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co
administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy
volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and
20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged
upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg
with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in
elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide
alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be
monitored for alterations in serum concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from
26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced
when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic
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epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See
lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID
for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30%
decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose
excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate
serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for
neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate
dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co
administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was
associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume
of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent
volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of
valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added
to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is
unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic
relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted
in patients taking anticoagulants.
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Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by
38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently
administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with
clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers
(n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers
(n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on
valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and
without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)].
Concomitant administration of topiramate with valproate has also been associated with hypothermia in
patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients
in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)].
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should encourage pregnant
patients taking Depakene to enroll in the NAAED Pregnancy Registry. This can be done by calling toll free 1
888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at
the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other
adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication
increases the risk of congenital malformations, particularly neural tube defects, but also malformations
involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major
structural abnormalities is greatest during the first trimester; however, other serious developmental effects
can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born
to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than
the rate among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. [see Warnings and Precautions (5.3)].
In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated
behavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal valproate
use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%,
compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in
10,000 births).
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• To prevent major seizures, women with epilepsy should not discontinue Depakene abruptly, as this can
precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor
seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the
drug may be considered prior to and during pregnancy in individual cases if the seizure disorder
severity and frequency do not pose a serious threat to the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered to
pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
pregnancy decreases the risk for congenital neural tube defects in the general population. It is not
known whether the risk of neural tube defects in the offspring of women receiving valproate is
reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception
and during pregnancy should be routinely recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A
patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth
to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in
pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also
been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of
neural tube defects and other structural abnormalities. Based on published data from the CDC’s National
Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%.
The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to
2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal
valproate exposure were reported among offspring of 149 enrolled women who used valproate during
pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial
defects, cardiovascular malformations and malformations of varying severity involving other body systems.
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The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% – 16.9%)
in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during
pregnancy (dose range 500 – 2000 mg/day). The major malformation rate among the internal comparison
group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy
was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following
exposure in utero to any other antiepileptic drug monotherapy.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
States and United Kingdom that found that children with prenatal exposure to valproate had lower
Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98
104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94-104]). The D.A.S., which has
a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The
D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ
testing and generally correlates with IQ scores later in childhood.
Although all of the available studies have methodological limitations, the weight of the evidence supports a
causal association between valproate exposure in utero and subsequent adverse effects on cognitive
development.
There are published case reports of fatal hepatic failure in offspring of women who used valproate during
pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal
structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment
of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body
surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac,
and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been
reported following valproate administration during critical periods of organogenesis, and the teratogenic
response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor,
and social interaction deficits) and brain histopathological changes have also been reported in mice and rat
offspring exposed prenatally to clinically relevant doses of valproate.
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8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing
woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk
of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning].
When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to
attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and
10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of
10 years, children have pharmacokinetic parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid
concentrations. Interpretation of valproic acid concentrations in children should include consideration of
factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication
of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric
patients were shown to be comparable to those in adults [see Adverse Reactions (6)].
Nonclinical Developmental Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal
dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated
during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was
less than the maximum recommended human dose on a mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania
associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65
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years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain,
somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether
these events indicate additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for
somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and
dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage
and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been
reported; however, patients have recovered from valproate levels as high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem
hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or
emesis will vary with the time since ingestion. General supportive measures should be applied with particular
attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone
could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients
with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also known as
dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic
odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule contains 250
mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben,
and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and
natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate
exerts its antiepileptic effects have not been established. It has been suggested that its activity in epilepsy is
related to increased brain concentrations of gamma-aminobutyric acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented. One
contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the
clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the
bioactive valproate species.
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For example, because the plasma protein binding of valproate is concentration dependent, the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free
fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate, although some
patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules
deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may
vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or
postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food
or the capsule is taken intact), these differences should be of minor clinical importance under the steady state
conditions achieved in chronic use in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax could be
important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater
influence on the rate of absorption of the Depakote tablet (increase in Tmax from 4 to 8 hours) than on the
absorption of the Depakote sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with
dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be
affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in
primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability
(extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma
peak to trough concentrations between valproate formulations are inconsequential from a practical clinical
standpoint.
Co-administration of oral valproate products with food and substitution among the various Depakote and
Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see
Dosage and Administration (2.1)]. Nonetheless, any changes in dosage administration, or the addition or
discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status
and valproate plasma concentrations.
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Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction increases from
approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the
elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of
other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin,
carbamazepine, warfarin, and tolbutamide). (See Drug Interactions (7.2) for more detailed information on the
pharmacokinetic interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about
10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an
administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major
metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is
eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in
urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase
proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding.
The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2,
respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92
L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing
regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing
enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine,
phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate
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clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant
antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate valproate compared
to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of
glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased
volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-
life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children
greater than 2 months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e.,
mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that
approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be
reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free
fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and
Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and females (4.8
± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
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Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.3)]. Liver disease impairs the
capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7
patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that
study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with
decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate.
Accordingly, monitoring of total concentrations may be misleading since free concentrations may be
substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure
(creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by
about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein
binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum
recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the
incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend
for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for
humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects
in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats.
Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children
taking valproate, but this association was not observed in another study conducted in adults. There is some
evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an
increase in SCE frequency is not known.
Fertility
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NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 36 of 48
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately
equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150
mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility
studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately
equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on
sperm production and fertility in humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur in isolation or
in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients
who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses
of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range"
were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo.
Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.
Table 5: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex
partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A
positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative
percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is
shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any
particular level of improvement was consistently higher for Depakote than for placebo. For example, 45% of
patients treated with Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of
patients treated with placebo.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 37 of 48 Graphic of percent of patients on X axis, reduction in CPS rate on Y access
The second study assessed the capacity of Depakote to reduce the incidence of CPS when administered as the
sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose
treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they
continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with
adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized phase were then
brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an
interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In
patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy
were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-randomization
assessment.
Table 6: Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 38 of 48
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex
partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive
percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent
reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is
shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients
achieving any particular level of reduction was consistently higher for high dose Depakote than for low dose
Depakote. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a reduction in
complex partial seizure rates compared to 54% of patients receiving low dose Depakote. % of patients on X access, percent reduction in CPS rate on Y access
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing
the trademark Depakene for product identification, in bottles of 100 capsules (NDC 0074-5681-13), and as a
red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of
16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
Reference ID: 3026475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 39 of 48
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly
[see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and
Precautions (5.4)].
17.3 Birth Defects and Neurobehavioral Development Adverse Effects
Prescribers should inform pregnant women and women of childbearing potential that use of Depakene during
pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers
should advise women to use effective contraception while using valproate. When appropriate, prescribers
should counsel these patients about alternative therapeutic options. This is particularly important when
valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs
during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific
Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Patients, their caregivers, and families should be counseled that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal
thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the
healthcare providers [see Warnings and Precautions (5.6)].
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 40 of 48
17.5 Hyperammonemia
Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and
be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)].
17.6 CNS depression
Since valproate products may produce CNS depression, especially when combined with another CNS
depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an
automobile or operating dangerous machinery, until it is known that they do not become drowsy from the
drug.
17.7 Multi-organ Hypersensitivity Reaction
Patients should be instructed that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see
Warnings and Precautions (5.11)].
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 41 of 48
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get a refill.
There may be new information. This information does not take the place of talking to your healthcare provider
about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years old.
The risk of getting this serious liver damage is more likely to happen within the first 6 months of
treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
Reference ID: 3026475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 42 of 48
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at
risk for serious birth defects. The most common birth defects with Depakote or Depakene affect
the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur
in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These
defects can begin in the first month, even before you know you are pregnant. Other birth defects
can happen.
o Birth defects may occur even in children born to women who are not taking any medicines and
do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the
chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at
risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of birth defects.
o All women of child-bearing age should talk to their healthcare provider about using other
possible treatments instead of Depakote or Depakene. If the decision is made to use
Depakote or Depakene, you should use effective birth control (contraception) unless you
are planning to become pregnant.
o Tell your healthcare provider right away if you become pregnant while taking Depakote or
Depakene. You and your healthcare provider should decide if you will continue to take Depakote
or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your
healthcare provider about registering with the North American Antiepileptic Drug Pregnancy
Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry
is to collect information about the safety of antiepileptic drugs during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a
very small number of people, about 1 in 500.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 43 of 48
Call a healthcare provider right away if you have any of these symptoms, especially if they are
new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or
Depakene suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has
epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or
actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 44 of 48
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or
with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in
Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and
Depakene.
• have a genetic problem called urea cycle disorder
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare
provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and non
prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each
time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider
will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 45 of 48
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew
Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can
not swallow Depakote or Depakene whole. You may need a different medicine.
• Depakote sprinkle capsules may be swallowed whole, or they may be opened and the contents may be
sprinkled on a small amount of soft food, such as applesauce or pudding. See the Patient Instructions
for Use at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle
capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control
Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other
medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your
doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may
make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affect
you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 950F, feeling tired,
confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin blistering and
peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat,
trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less
than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your
doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 46 of 48
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information, ask your
healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800
FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene to
other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Depakote or Depakene. If you
would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare
provider for information about Depakote or Depakene that is written for health professionals.
For more information, go to www.rxabbott.com or call 1-800-633-9110.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 47 of 48
What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline
cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide,
and triacetin. The 500 mg tablets also contain iron oxide and polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch
(contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron
oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol,
sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
500 mg is Mfd. By Abbott Laboratories, North Chicago, IL 60064 U.S.A. or
Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
For Abbott Laboratories, North Chicago, IL 60064 U.S.A.
Depakote Tablets
Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
Abbott Laboratories, North Chicago, IL 60064, U.S.A.Depakene Capsules
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 48 of 48
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Issued 10/2011 Abbott Laboratories
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:44:32.706254
|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid) capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence
seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
-------DOSAGE FORMS AND STRENGTHS------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------CONTRAINDICATIONS------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
• Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS------
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS------
• Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 06/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
Reference ID: 3528395
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
Reference ID: 3528395
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death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
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Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25%
every 2 weeks. This reduction may be started at initiation of Depakene therapy, or delayed by 1
to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and
duration of withdrawal of the concomitant AED can be highly variable, and patients should be
monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
Reference ID: 3528395
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regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
Reference ID: 3528395
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dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
Reference ID: 3528395
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For current labeling information, please visit https://www.fda.gov/drugsatfda
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
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5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
Reference ID: 3528395
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in
patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average,
had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had
treatment discontinued, with return of platelet counts to normal. In the remaining patients,
platelet counts normalized with continued treatment. In this study, the probability of
thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110
mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the
higher doses should therefore be weighed against the possibility of a greater incidence of adverse
effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
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with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
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5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
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Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
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Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
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Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
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Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience
The following adverse reactions have been identified during post approval use of Depakote.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens-
Johnson syndrome. Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility,
and behavioral deterioration.
Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and
weakness.
Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia,
eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow
suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid
gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia,
hyperglycinemia, and inappropriate ADH secretion.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss.
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Other: Allergic reaction, anaphylaxis, developmental delay, autism and/or autism spectrum
disorder, bone pain, bradycardia, and cutaneous vasculitis.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
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A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
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postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
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therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
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Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
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Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
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• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
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following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
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In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
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The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
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Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
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There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
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Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
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0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-AXXX June 2014
Reference ID: 3528395
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:44:32.788057
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018081s049,018082s034lbl.pdf', 'application_number': 18081, 'submission_type': 'SUPPL ', 'submission_number': 49}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid) capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
•
Hepatotoxicity, including fatalities, usually during first 6 months
of treatment. Children under the age of two years and patients
with mitochondrial disorders are at higher risk. Monitor patients
closely, and perform serum liver testing prior to therapy and at
frequent intervals thereafter (5.1)
•
Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
•
Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depakene is an anti-epileptic drug indicated for:
•
Monotherapy and adjunctive therapy of complex partial seizures; sole
and adjunctive therapy of simple and complex absence seizures;
adjunctive therapy in patients with multiple seizure types that include
absence seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depakene is intended for oral administration. (2.1)
•
Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure
control or limiting side effects (2.1)
•
Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
-------DOSAGE FORMS AND STRENGTHS------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------CONTRAINDICATIONS------
•
Hepatic disease or significant hepatic dysfunction (4, 5.1)
•
Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
•
Suspected POLG-related disorder in children under two years of age (4,
5.1)
•
Known hypersensitivity to the drug (4, 5.12)
•
Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS------
•
Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
•
Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are
unacceptable; should not be administered to a woman of childbearing
potential unless essential (5.2, 5.3, 5.4)
•
Pancreatitis; Depakene should ordinarily be discontinued (5.5)
•
Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
•
Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
•
Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in
mental status (5.6, 5.9, 5.10)
•
Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
•
Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
•
Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS------
•
Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
•
The safety and tolerability of valproate in pediatric patients were shown
to be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS------
•
Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
•
Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations
is recommended (7.1)
•
Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by
inhibiting their metabolism or protein binding displacement (7.2)
•
Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
•
Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS------
•
Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
•
Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
•
Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: 07/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
Reference ID: 3349699
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2 Mania
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
* Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
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Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
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100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
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Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
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both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
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5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
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POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
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carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
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5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per 1000
Patients
Drug Patients with
Events Per 1000
Patients
Relative Risk: Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference: Additional
Drug Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
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during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients
with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at
least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment
discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts
normalized with continued treatment. In this study, the probability of thrombocytopenia
appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or
≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should
therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
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underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
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days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
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5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
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were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled
Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
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not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of
Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or
greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
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Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
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Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea,
vomiting, and indigestion. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia
with some weight loss and increased appetite with weight gain have also been reported. The
administration of delayed-release divalproex sodium may result in reduction of gastrointestinal
side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most
often in patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
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particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema
multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been
reported including a fatal case in a 6 month old infant taking valproate and several other
concomitant medications. An additional case of toxic epidermal necrosis resulting in death was
reported in a 35 year old patient with AIDS taking several concomitant medications and with a
history of multiple cutaneous drug reactions. Serious skin reactions have been reported with
concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and
behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis,
and frank hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and
appear to be dose-related. Occasionally, laboratory test results include increases in serum
bilirubin and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.5)].
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Metabolic: Hyperammonemia [see Warnings and Precautions (5.9)], hyponatremia, and
inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a
cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain,
cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and
hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
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The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
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Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
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amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
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concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
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In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
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7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
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Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially
important when valproate use is considered for a condition not usually associated
with permanent injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who
plan to become pregnant unless other treatments have failed to provide adequate
symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks. When
treating a pregnant woman or a woman of childbearing potential, carefully consider
both the potential risks and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
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• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
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104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
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Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
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8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
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For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
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dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
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(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
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Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
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Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
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Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase Incidence
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Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
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15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
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Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
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Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
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Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with
Depakote or Depakene affect the brain and spinal cord and are called spina bifida or
neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to
mothers who use this medicine during pregnancy. These defects can begin in the first
month, even before you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy
can lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of
causing birth defects and decreased IQ in your child.
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
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o All women of child-bearing age should talk to their healthcare provider about
using other possible treatments instead of Depakote or Depakene. If the decision
is made to use Depakote or Depakene, you should use effective birth control
(contraception).
o Tell your healthcare provider right away if you become pregnant while taking
Depakote or Depakene. You and your healthcare provider should decide if you will
continue to take Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene,
talk to your healthcare provider about registering with the North American
Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1
888-233-2334. The purpose of this registry is to collect information about the safety
of antiepileptic drugs during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
Reference ID: 3349699
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o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors,
thoughts, or feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Reference ID: 3349699
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Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
Reference ID: 3349699
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• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
Reference ID: 3349699
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• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Reference ID: 3349699
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
Reference ID: 3349699
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dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote Sprinkle Capsules
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A816 July 2013
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018081s056lbl.pdf', 'application_number': 18081, 'submission_type': 'SUPPL ', 'submission_number': 56}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid), capsules, USP, for oral use
DEPAKENE (valproic acid) oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
RECENT MAJOR CHANGES
Warnings and Precautions, Birth Defects (5.2)
1/2015
Warnings and Precautions, Bleeding and Other Hematopeietic
1/2015
Disorders (5.8)
Warnings and Precautions, Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reaction
1/2015
(5.12)
INDICATIONS AND USAGE
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence seizures
(1)
DOSAGE AND ADMINISTRATION
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
DOSAGE FORMS AND STRENGTHS
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
CONTRAINDICATIONS
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial DNA
polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
WARNINGS AND PRECAUTIONS
• Hepatotoxicity; evaluate high risk populations and monitor serum liver tests
(5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Bleeding and other hematopoietic disorders; monitor platelet counts and
coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy with
or without associated hyperammonemia. This adverse reaction can also
occur in patients using concomitant topiramate (5.11)
• Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan hypersensitivity reaction; discontinue Depakene
(5.12)
• Somnolence in the elderly can occur. Depakene dosage should be increased
slowly and with regular monitoring for fluid and nutritional intake (5.14)
ADVERSE REACTIONS
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance, while
enzyme inhibitors (e.g., felbamate) can decrease valproate clearance.
Therefore increased monitoring of valproate and concomitant drug
concentrations and dosage adjustment are indicated whenever enzyme-
inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine
may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
USE IN SPECIFIC POPULATIONS
• Pregnancy: Depakene can cause congenital malformations including neural
tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid
and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 1/2015
Reference ID: 3683242
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Bleeding and Other Hematopoietic Disorders
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3683242
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
Reference ID: 3683242
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For current labeling information, please visit https://www.fda.gov/drugsatfda
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
Reference ID: 3683242
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
Reference ID: 3683242
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
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dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
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anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
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5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The
rate of congenital malformations among babies born to mothers using valproate is about four
times higher than the rate among babies born to epileptic mothers using other anti-seizure
monotherapies. Evidence suggests that folic acid supplementation prior to conception and during
the first trimester of pregnancy decreases the risk for congenital neural tube defects in the
general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Bleeding and Other Hematopoietic Disorders
Valproate is associated with dose-related thrombocytopenia. In a clinical trial of Depakote
(divalproex sodium) as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving
approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L.
Approximately half of these patients had treatment discontinued, with return of platelet counts to
normal. In the remaining patients, platelet counts normalized with continued treatment. In this
study, the probability of thrombocytopenia appeared to increase significantly at total valproate
concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit
which may accompany the higher doses should therefore be weighed against the possibility of a
greater incidence of adverse effects. Valproate use has also been associated with decreases in
other cell lines and myelodysplasia.
Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired
von Willebrand’s disease), measurements of complete blood counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended that patients
receiving Depakene (valproic acid) be monitored for blood counts and coagulation parameters
prior to planned surgery and during pregnancy [see Use in Specific Populations (8.1)]. Evidence
of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of
the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
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not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity Reactions
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy, in association with other organ system involvement, such as hepatitis,
nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute
viral infection. Eosinophilia is often present. Because this disorder is variable in its expression,
other organ systems not noted here may be involved. It is important to note that early
manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even
though rash is not evident. If such signs or symptoms are present, the patient should be evaluated
immediately. Valproate should be discontinued and not be resumed if an alternative etiology for
the signs or symptoms cannot be established.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
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higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
• Hepatic failure [see Warnings and Precautions (5.1)]
• Birth defects [see Warnings and Precautions (5.2)]
• Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
• Pancreatitis [see Warnings and Precautions (5.5)]
• Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
• Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
• Hypothermia [see Warnings and Precautions (5.11)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
hypersensitivity reactions [see Warnings and Precautions (5.12)]
• Somnolence in the elderly [see Warnings and Precautions (5.14)]
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Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
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Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
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Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
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6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience
The following adverse reactions have been identified during post approval use of Depakote.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens-
Johnson syndrome.
Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility,
disturbance in attention, learning disorder, and behavioral deterioration.
Neurologic: There have been several reports of acute or subacute cognitive decline and
behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated
with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy
reversed partially or fully after valproate discontinuation.
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Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and
weakness.
Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic
with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia,
agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid
gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia,
hyperglycinemia, and inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss.
Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and
cutaneous vasculitis.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For
example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance
of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher
concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
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valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
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7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
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lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
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Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
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To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations, hypospadias, limb malformations). The risk of major structural abnormalities is
greatest during the first trimester; however, other serious developmental effects can occur with
valproate use throughout pregnancy. The rate of congenital malformations among babies born to
epileptic mothers who used valproate during pregnancy has been shown to be about four times
higher than the rate among babies born to epileptic mothers who used other anti-seizure
monotherapies [see Warnings and Precautions (5.3)].
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
An observational study has suggested that exposure to valproate products during pregnancy may
increase the risk of autism spectrum disorders. In this study, children born to mothers who had
used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]:
1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not
exposed to valproate products during pregnancy. The absolute risks for autism spectrum
disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI:
1.5%-1.6%) in children not exposed to valproate products. Because the study was observational
in nature, conclusions regarding a causal association between in utero valproate exposure and an
increased risk of autism spectrum disorder cannot be considered definitive.
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
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• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Pregnant women taking valproate may develop clotting abnormalities including
thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which
may result in hemorrhagic complications in the neonate including death [see Warnings and
Precautions (5.8)]. If valproate is used in pregnancy, the clotting parameters should be
monitored carefully in the mother. If abnormal in the mother, then these parameters should
also be monitored in the neonate.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
• Hypoglycemia has been reported in neonates whose mothers have taken valproate during
pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the
offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during
pregnancy. These data show up to a five-fold increased risk for any major malformation
following valproate exposure in utero compared to the risk following exposure in utero to other
antiepileptic drugs taken in monotherapy. The major congenital malformations included cases of
neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts,
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craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and
malformations of varying severity involving other body systems.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
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patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
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these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
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Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
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Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
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Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
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phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
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15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
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Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
Multiorgan Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
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Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium delayed release capsules)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
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◦ nausea or vomiting that does not go away
◦ loss of appetite
◦ pain on the right side of your stomach (abdomen)
◦ dark urine
◦ swelling of your face
◦ yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
◦ If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects that affect the brain and spinal cord and are called
spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies
born to mothers who use this medicine during pregnancy. These defects can begin in the
first month, even before you know you are pregnant. Other birth defects that affect the
structures of the heart, head, arms, legs, and the opening where the urine comes out
(urethra) on the bottom of the penis can also happen.
◦ Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
◦ Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
◦ If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
◦ There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
◦ Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
◦ All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
◦ Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
◦ Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
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◦ thoughts about suicide or dying
◦ attempts to commit suicide
◦ new or worse depression
◦ new or worse anxiety
◦ feeling agitated or restless
◦ panic attacks
◦ trouble sleeping (insomnia)
◦ new or worse irritability
◦ acting aggressive, being angry, or violent
◦ acting on dangerous impulses
◦ an extreme increase in activity and talking (mania)
◦ other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
◦ Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
◦ Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
◦ complex partial seizures in adults and children 10 years of age and older
◦ simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
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• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you cannot swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
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What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your
joints due to bleeding or bleeding from your mouth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
Reference ID: 3683242
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These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
Reference ID: 3683242
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: January 2015
Reference ID: 3683242
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:33.255378
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018081s059,018082s042lbl.pdf', 'application_number': 18081, 'submission_type': 'SUPPL ', 'submission_number': 59}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid), capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
----------------------------INDICATIONS AND USAGE---------------------------
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence
seizures (1)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
----------------------DOSAGE FORMS AND STRENGTHS--------------------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------------------------------CONTRAINDICATIONS-----------------------------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
------------------------WARNINGS AND PRECAUTIONS----------------------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
• Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------------------------------ADVERSE REACTIONS-----------------------------
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------------------------------DRUG INTERACTIONS-----------------------------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
------------------------USE IN SPECIFIC POPULATIONS----------------------
• Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 11/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
5.8 Thrombocytopenia
1 INDICATIONS AND USAGE
5.9 Hyperammonemia
1.1 Epilepsy
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
1.2 Important Limitations
Topiramate Use
2 DOSAGE AND ADMINISTRATION
5.11 Hypothermia
2.1 Epilepsy
5.12 Multi-Organ Hypersensitivity Reactions
2.2 General Dosing Advice
5.13 Interaction with Carbapenem Antibiotics
3 DOSAGE FORMS AND STRENGTHS
5.14 Somnolence in the Elderly
4 CONTRAINDICATIONS
5.15 Monitoring: Drug Plasma Concentration
5 WARNINGS AND PRECAUTIONS
5.16 Effect on Ketone and Thyroid Function Tests
5.1 Hepatotoxicity
5.17 Effect on HIV and CMV Viruses Replication
5.2 Birth Defects
6 ADVERSE REACTIONS
5.3 Decreased IQ Following in utero Exposure
6.1 Epilepsy
5.4 Use in Women of Childbearing Potential
6.2 Mania
5.5 Pancreatitis
6.3 Migraine
5.6 Urea Cycle Disorders (UCD)
6.4 Post-Marketing Experience
5.7 Suicidal Behavior and Ideation
7 DRUG INTERACTIONS
Reference ID: 3660954
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3660954
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
Reference ID: 3660954
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
Reference ID: 3660954
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25%
every 2 weeks. This reduction may be started at initiation of Depakene therapy, or delayed by 1
to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and
duration of withdrawal of the concomitant AED can be highly variable, and patients should be
monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
Reference ID: 3660954
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
Reference ID: 3660954
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
Reference ID: 3660954
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
Reference ID: 3660954
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in
patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average,
had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had
treatment discontinued, with return of platelet counts to normal. In the remaining patients,
platelet counts normalized with continued treatment. In this study, the probability of
thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110
mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the
higher doses should therefore be weighed against the possibility of a greater incidence of adverse
effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
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with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
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5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
The following serious adverse reactions are described below and elsewhere in the labeling:
Hepatic failure [see Warnings and Precautions (5.1)]
Birth defects [see Warnings and Precautions (5.2)]
Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
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Pancreatitis [see Warnings and Precautions (5.5)]
Hyperammonemic encephalopathy [see Warnings and Precautions (5.6), (5.9), (5.10)]
Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
Thrombocytopenia [see Warnings and Precautions (5.8)]
Hypothermia [see Warnings and Precuations (5.11)]
Multi-organ hypersensitivity reactions [see Warnings and Precautions (5.12)]
Somnolence in the elderly [see Warnings and Precautions (5.14)]
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
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Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
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Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
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Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience
The following adverse reactions have been identified during post approval use of Depakote.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens-
Johnson syndrome.
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Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Neurologic: There have been several reports of acute or subacute cognitive decline and
behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated
with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy
reversed partially or fully after valproate discontinuation.Musculoskeletal: Fractures, decreased
bone mineral density, osteopenia, osteoporosis, and weakness.
Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia,
eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow
suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid
gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia,
hyperglycinemia, and inappropriate ADH secretion.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss.
Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and
cutaneous vasculitis.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
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A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
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Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
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Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
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In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies [see
Warnings and Precautions (5.3)].
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
An observational study has suggested that exposure to valproate products during pregnancy may
increase the risk of autism spectrum disorders. In this study, children born to mothers who had
used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]:
1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not
exposed to valproate products during pregnancy. The absolute risks for autism spectrum
disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI:
1.5%-1.6%) in children not exposed to valproate products. Because the study was observational
in nature, conclusions regarding a causal association between in utero valproate exposure and an
increased risk of autism spectrum disorder cannot be considered definitive.
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
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• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
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included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
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8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
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8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
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should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
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Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
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decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
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14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
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0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
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17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium delayed release capsules)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
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Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
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o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
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Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
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• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
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The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
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For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-AXXX Month Year
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|
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018081s058,018082s041lbl.pdf', 'application_number': 18081, 'submission_type': 'SUPPL ', 'submission_number': 58}
|
11,148
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NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 3 of 48
FULL PRESCRIBING INFORMATION
BOXED WARNING
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. Children under the age of two
years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple
anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by
mental retardation, and those with organic brain disease. When Depakene products are used in this patient
group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed
against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and
vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored
closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at
frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida).
Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the
management of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective
contraception while using valproate. [see Warnings and Precautions (5.2), 5.3].
A Medication Guide describing the risks of valproate is available for patients. [see Patient Counseling
Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 4 of 48
have been reported shortly after initial use as well as after several years of use. Patients and guardians should be
warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require
prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative
treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and
Precautions (5.4)].
1 INDICATIONS AND USAGE
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of patients with
complex partial seizures that occur either in isolation or in association with other types of seizures. Depakene
(valproic acid) is indicated for use as sole and adjunctive therapy in the treatment of simple and complex
absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by
certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term
used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole without chewing
to avoid local irritation of the mouth and throat.
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it should be taken as
soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double
the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and
pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakene
dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide,
phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
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Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15
mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.
Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not they are in the
usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate
for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations
above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher
doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week
to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No
recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.
This reduction may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a
concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this period for
increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be
increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma
levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50
to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day
can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either
carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of carbamazepine or phenytoin
dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other
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concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of
concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until
seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60
mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.
However, therapeutic valproate serum concentration for most patients with absence seizures is considered to
range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations
[see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to
prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant
hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15 mg/kg/day):
Table 1: Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the
elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and
with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.
Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid
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intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the
basis of both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-
related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations
of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of
improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence
of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly
building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing
the trademark Depakene for product identification, in bottles of 100 capsules and as a red Oral Solution
containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
Depakene should not be administered to patients with hepatic disease or significant hepatic dysfunction [see
Warnings and Precautions (5.1)].
Depakene is contraindicated in patients with known hypersensitivity to the drug [see Warnings and
Precautions (5.11)].
Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions
(5.5)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have
occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non
specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with
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epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter,
especially during the first six months. However, healthcare providers should not rely totally on serum
biochemistry since these tests may not be abnormal in all instances, but should also consider the results of
careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior history of hepatic
disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with
severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at
particular risk. Experience has indicated that children under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When
Depakene products are used in this patient group, they should be used with extreme caution and as a sole
agent. The benefits of therapy should be weighed against the risks. Above this age group, experience has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or
apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed
Warning and Contraindications (4)].
5.2 Use in Women of Childbearing Potential
Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may
occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential
unless the drug is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
migraine). Women should use effective contraception while using valproate. Women who are planning a
pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy,
and alternative therapeutic options should be considered for these patients. [see Boxed Warning and Use in
Specific Populations (8.1)].
To prevent major seizures, Depakene should not be discontinued abruptly, as this can precipitate status
epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
pregnancy decreases the risk for congenital neural tube defects in the general population.
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5.3 Birth Defects and Neurobehavioral Adverse Effects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that
maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial
defects, cardiovascular malformations and malformations involving various body systems). The rate of
congenital malformations among babies born to mothers using valproate is about four times higher than the
rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that
folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk
for congenital neural tube defects in the general population.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
States and United Kingdom that found that children with prenatal exposure to valproate had lower
Differential Ability Scale (D.A.S) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal
exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98
104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which
has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years.
The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo
IQ testing and generally correlates with IQ scores later in childhood.
Although all of the available studies have methodological limitations, the weight of the evidence supports
the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development.
In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and
demonstrated behavioral deficits. [see Use in Specific Populations (8.1)]
5.4 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some
cases have occurred shortly after initial use as well as after several years of use. The rate based upon the
reported cases exceeds that expected in the general population and there have been cases in which pancreatitis
recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without
alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians
should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.
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Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see
Boxed Warning].
5.5 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate
therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly
ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should
be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma,
encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained
mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and
lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of
UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or
symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while
receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy)
and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and
Precautions (5.9)].
5.6 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored
for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in
mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after
starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials
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included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24
weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications
suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5
100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
Drug Patients
Relative Risk: Incidence of Events in
Risk Difference:
with Events Per
with Events Per
Drug Patients/Incidence in Placebo
Additional Drug
1000 Patients
1000 Patients
Patients
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical
trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and
psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed
are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and
behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider
whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
5.7 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-
related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients with epilepsy, 34/126
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patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x
109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to
normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the
probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110
mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses
should therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving
Depakene (valproic acid) be monitored for platelet count and coagulation parameters prior to planned surgery.
Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the
dosage or withdrawal of therapy.
5.8 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal
liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status,
hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and
Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate
interventions for treatment of hyperammonemia should be initiated, and such patients should undergo
investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions
(5.5, 5.8, 5.9)].
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of
plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or
without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of
hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive
function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see
Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either
drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate
monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced
hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without
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encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing
defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy,
vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)].
5.10 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in
association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This
adverse reaction can also occur in patients using concomitant topiramate with valproate after starting
topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)].
Consideration should be given to stopping valproate in patients who develop hypothermia, which may be
manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant
alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical
management and assessment should include examination of blood ammonia levels.
5.11 Multi-organ Hypersensitivity Reaction
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation
of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days).
Although there have been a limited number of reports, many of these cases resulted in hospitalization and at
least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients
typically, although not exclusively, presented with fever and rash associated with other organ system
involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test
abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus,
nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected,
valproate should be discontinued and an alternative treatment started. Although the existence of cross
sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated
with multi-organ hypersensitivity would indicate this to be a possibility.
5.12 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may
reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum
valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative
antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop
significantly or seizure control deteriorates [see Drug Interactions (7.1)].
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5.13 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses
were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate
patients had somnolence compared to placebo, and although not statistically significant, there was a higher
proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than
with placebo. In some patients with somnolence (approximately one-half), there was associated reduced
nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients,
dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should
be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see
Dosage and Administration (2.2)].
5.14 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme induction,
periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the
early course of therapy [see Drug Interactions (7)].
5.15 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of
the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of
these is unknown.
5.16 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under
certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of
these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy.
Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the
viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
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6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may
not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium) tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote
was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was
the primary reason for discontinuation in the Depakote -treated patients (6%), compared to 1% of placebo-
treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote -treated patients
and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive
therapy for the treatment of complex partial seizures. Since patients were also treated with other antiepilepsy
drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to
Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive
Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
Placebo (%)
(n = 77)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
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Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose
Depakote group, and for which the incidence was greater than in the low dose group, in a controlled trial of
Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another
antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the
following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other
antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Depakote Monotherapy
for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
Low Dose (%)
(n = 131)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
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Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater
incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358
patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal
dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
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6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic episodes
associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more
of patients from two placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine
headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two
placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous
reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea, vomiting,
and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea,
abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased
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appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium
may result in reduction of gastrointestinal side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic
medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis,
"spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and Parkinsonism
have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate
alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has
developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following drug
withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in
patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case
in a 6 month old infant taking valproate and several other concomitant medications. An additional case of
toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several
concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have
been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be
reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage
[see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis,
hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency,
bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be
dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes
in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and
Precautions (5.1)].
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Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not
been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.4)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and inappropriate ADH
secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent
nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of
women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of
glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine,
and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will
generally have longer half-lives and higher concentrations than patients receiving polytherapy with
antiepilepsy drugs.
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In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to
have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a
relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations
should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed
medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions
are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to
pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate.
Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β
oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was
decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin.
Caution should be observed if valproate and aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving
carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may
result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid
concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or
anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure
control deteriorates [see Warnings and Precautions (5.12)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy
(n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL)
compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak
concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when
felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily
dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage
adjustment may be necessary when it is co-administered with rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox,
Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients
already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already
receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on
the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not
exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
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Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females)
who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a
34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate
and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate
and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be
considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E)
increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a history of
absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co
administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy
volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and
20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged
upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg
with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in
elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide
alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be
monitored for alterations in serum concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from
26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced
when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic
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epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See
lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID
for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30%
decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose
excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate
serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for
neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate
dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co
administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was
associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume
of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent
volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of
valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added
to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is
unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic
relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted
in patients taking anticoagulants.
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Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by
38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently
administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with
clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers
(n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers
(n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on
valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and
without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)].
Concomitant administration of topiramate with valproate has also been associated with hypothermia in
patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients
in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)].
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should encourage pregnant
patients taking Depakene to enroll in the NAAED Pregnancy Registry. This can be done by calling toll free 1
888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at
the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other
adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication
increases the risk of congenital malformations, particularly neural tube defects, but also malformations
involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major
structural abnormalities is greatest during the first trimester; however, other serious developmental effects
can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born
to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than
the rate among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. [see Warnings and Precautions (5.3)].
In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated
behavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal valproate
use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%,
compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in
10,000 births).
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• To prevent major seizures, women with epilepsy should not discontinue Depakene abruptly, as this can
precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor
seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the
drug may be considered prior to and during pregnancy in individual cases if the seizure disorder
severity and frequency do not pose a serious threat to the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered to
pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
pregnancy decreases the risk for congenital neural tube defects in the general population. It is not
known whether the risk of neural tube defects in the offspring of women receiving valproate is
reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception
and during pregnancy should be routinely recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A
patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth
to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in
pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also
been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of
neural tube defects and other structural abnormalities. Based on published data from the CDC’s National
Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%.
The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to
2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal
valproate exposure were reported among offspring of 149 enrolled women who used valproate during
pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial
defects, cardiovascular malformations and malformations of varying severity involving other body systems.
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The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% – 16.9%)
in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during
pregnancy (dose range 500 – 2000 mg/day). The major malformation rate among the internal comparison
group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy
was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following
exposure in utero to any other antiepileptic drug monotherapy.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
States and United Kingdom that found that children with prenatal exposure to valproate had lower
Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98
104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94-104]). The D.A.S., which has
a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The
D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ
testing and generally correlates with IQ scores later in childhood.
Although all of the available studies have methodological limitations, the weight of the evidence supports a
causal association between valproate exposure in utero and subsequent adverse effects on cognitive
development.
There are published case reports of fatal hepatic failure in offspring of women who used valproate during
pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal
structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment
of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body
surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac,
and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been
reported following valproate administration during critical periods of organogenesis, and the teratogenic
response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor,
and social interaction deficits) and brain histopathological changes have also been reported in mice and rat
offspring exposed prenatally to clinically relevant doses of valproate.
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8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing
woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk
of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning].
When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to
attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and
10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of
10 years, children have pharmacokinetic parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid
concentrations. Interpretation of valproic acid concentrations in children should include consideration of
factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication
of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric
patients were shown to be comparable to those in adults [see Adverse Reactions (6)].
Nonclinical Developmental Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal
dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated
during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was
less than the maximum recommended human dose on a mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania
associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65
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years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain,
somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether
these events indicate additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for
somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and
dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage
and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been
reported; however, patients have recovered from valproate levels as high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem
hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or
emesis will vary with the time since ingestion. General supportive measures should be applied with particular
attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone
could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients
with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also known as
dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic
odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule contains 250
mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben,
and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and
natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate
exerts its antiepileptic effects have not been established. It has been suggested that its activity in epilepsy is
related to increased brain concentrations of gamma-aminobutyric acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented. One
contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the
clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the
bioactive valproate species.
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For example, because the plasma protein binding of valproate is concentration dependent, the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free
fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate, although some
patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules
deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may
vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or
postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food
or the capsule is taken intact), these differences should be of minor clinical importance under the steady state
conditions achieved in chronic use in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax could be
important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater
influence on the rate of absorption of the Depakote tablet (increase in Tmax from 4 to 8 hours) than on the
absorption of the Depakote sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with
dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be
affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in
primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability
(extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma
peak to trough concentrations between valproate formulations are inconsequential from a practical clinical
standpoint.
Co-administration of oral valproate products with food and substitution among the various Depakote and
Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see
Dosage and Administration (2.1)]. Nonetheless, any changes in dosage administration, or the addition or
discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status
and valproate plasma concentrations.
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Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction increases from
approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the
elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of
other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin,
carbamazepine, warfarin, and tolbutamide). (See Drug Interactions (7.2) for more detailed information on the
pharmacokinetic interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about
10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an
administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major
metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is
eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in
urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase
proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding.
The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2,
respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92
L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing
regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing
enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine,
phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate
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clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant
antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate valproate compared
to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of
glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased
volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-
life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children
greater than 2 months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e.,
mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that
approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be
reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free
fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and
Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and females (4.8
± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
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Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.3)]. Liver disease impairs the
capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7
patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that
study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with
decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate.
Accordingly, monitoring of total concentrations may be misleading since free concentrations may be
substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure
(creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by
about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein
binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum
recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the
incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend
for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for
humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects
in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats.
Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children
taking valproate, but this association was not observed in another study conducted in adults. There is some
evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an
increase in SCE frequency is not known.
Fertility
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Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately
equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150
mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility
studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately
equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on
sperm production and fertility in humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur in isolation or
in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients
who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses
of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range"
were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo.
Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.
Table 5: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex
partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A
positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative
percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is
shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any
particular level of improvement was consistently higher for Depakote than for placebo. For example, 45% of
patients treated with Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of
patients treated with placebo.
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Page 37 of 48 Graphic of percent of patients on X axis, reduction in CPS rate on Y access
The second study assessed the capacity of Depakote to reduce the incidence of CPS when administered as the
sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose
treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they
continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with
adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized phase were then
brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an
interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In
patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy
were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-randomization
assessment.
Table 6: Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex
partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive
percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent
reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is
shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients
achieving any particular level of reduction was consistently higher for high dose Depakote than for low dose
Depakote. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a reduction in
complex partial seizure rates compared to 54% of patients receiving low dose Depakote. % of patients on X access, percent reduction in CPS rate on Y access
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing
the trademark Depakene for product identification, in bottles of 100 capsules (NDC 0074-5681-13), and as a
red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of
16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
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17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly
[see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and
Precautions (5.4)].
17.3 Birth Defects and Neurobehavioral Development Adverse Effects
Prescribers should inform pregnant women and women of childbearing potential that use of Depakene during
pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers
should advise women to use effective contraception while using valproate. When appropriate, prescribers
should counsel these patients about alternative therapeutic options. This is particularly important when
valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs
during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific
Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Patients, their caregivers, and families should be counseled that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal
thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the
healthcare providers [see Warnings and Precautions (5.6)].
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17.5 Hyperammonemia
Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and
be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)].
17.6 CNS depression
Since valproate products may produce CNS depression, especially when combined with another CNS
depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an
automobile or operating dangerous machinery, until it is known that they do not become drowsy from the
drug.
17.7 Multi-organ Hypersensitivity Reaction
Patients should be instructed that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see
Warnings and Precautions (5.11)].
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MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get a refill.
There may be new information. This information does not take the place of talking to your healthcare provider
about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years old.
The risk of getting this serious liver damage is more likely to happen within the first 6 months of
treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
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o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at
risk for serious birth defects. The most common birth defects with Depakote or Depakene affect
the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur
in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These
defects can begin in the first month, even before you know you are pregnant. Other birth defects
can happen.
o Birth defects may occur even in children born to women who are not taking any medicines and
do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the
chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at
risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of birth defects.
o All women of child-bearing age should talk to their healthcare provider about using other
possible treatments instead of Depakote or Depakene. If the decision is made to use
Depakote or Depakene, you should use effective birth control (contraception) unless you
are planning to become pregnant.
o Tell your healthcare provider right away if you become pregnant while taking Depakote or
Depakene. You and your healthcare provider should decide if you will continue to take Depakote
or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your
healthcare provider about registering with the North American Antiepileptic Drug Pregnancy
Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry
is to collect information about the safety of antiepileptic drugs during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a
very small number of people, about 1 in 500.
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Call a healthcare provider right away if you have any of these symptoms, especially if they are
new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or
Depakene suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has
epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or
actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
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• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or
with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in
Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and
Depakene.
• have a genetic problem called urea cycle disorder
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare
provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and non
prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each
time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider
will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
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• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew
Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can
not swallow Depakote or Depakene whole. You may need a different medicine.
• Depakote sprinkle capsules may be swallowed whole, or they may be opened and the contents may be
sprinkled on a small amount of soft food, such as applesauce or pudding. See the Patient Instructions
for Use at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle
capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control
Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other
medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your
doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may
make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affect
you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 950F, feeling tired,
confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin blistering and
peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat,
trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less
than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your
doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
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• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information, ask your
healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800
FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene to
other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Depakote or Depakene. If you
would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare
provider for information about Depakote or Depakene that is written for health professionals.
For more information, go to www.rxabbott.com or call 1-800-633-9110.
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What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline
cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide,
and triacetin. The 500 mg tablets also contain iron oxide and polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch
(contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron
oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol,
sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
500 mg is Mfd. By Abbott Laboratories, North Chicago, IL 60064 U.S.A. or
Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
For Abbott Laboratories, North Chicago, IL 60064 U.S.A.
Depakote Tablets
Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
Abbott Laboratories, North Chicago, IL 60064, U.S.A.Depakene Capsules
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Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Issued 10/2011 Abbott Laboratories
This Medication Guide has been approved by the U.S. Food and Drug Administration.
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FULL PRESCRIBING INFORMATION
BOXED WARNING
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. Children under the age of two
years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple
anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by
mental retardation, and those with organic brain disease. When Depakene products are used in this patient
group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed
against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and
vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored
closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at
frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida).
Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the
management of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective
contraception while using valproate. [see Warnings and Precautions (5.2), 5.3].
A Medication Guide describing the risks of valproate is available for patients. [see Patient Counseling
Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases
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have been reported shortly after initial use as well as after several years of use. Patients and guardians should be
warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require
prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative
treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and
Precautions (5.4)].
1 INDICATIONS AND USAGE
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of patients with
complex partial seizures that occur either in isolation or in association with other types of seizures. Depakene
(valproic acid) is indicated for use as sole and adjunctive therapy in the treatment of simple and complex
absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by
certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term
used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole without chewing
to avoid local irritation of the mouth and throat.
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it should be taken as
soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double
the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and
pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Depakene
dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide,
phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
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Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15
mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.
Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not they are in the
usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate
for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations
above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher
doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week
to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No
recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.
This reduction may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a
concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this period for
increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be
increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma
levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50
to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day
can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving either
carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of carbamazepine or phenytoin
dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other
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concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of
concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until
seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60
mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.
However, therapeutic valproate serum concentration for most patients with absence seizures is considered to
range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations
[see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to
prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant
hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15 mg/kg/day):
Table 1: Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the
elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and
with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.
Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid
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intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the
basis of both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-
related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations
of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)]. The benefit of
improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence
of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly
building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing
the trademark Depakene for product identification, in bottles of 100 capsules and as a red Oral Solution
containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
Depakene should not be administered to patients with hepatic disease or significant hepatic dysfunction [see
Warnings and Precautions (5.1)].
Depakene is contraindicated in patients with known hypersensitivity to the drug [see Warnings and
Precautions (5.11)].
Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions
(5.5)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have
occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non
specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with
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epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter,
especially during the first six months. However, healthcare providers should not rely totally on serum
biochemistry since these tests may not be abnormal in all instances, but should also consider the results of
careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior history of hepatic
disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with
severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at
particular risk. Experience has indicated that children under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When
Depakene products are used in this patient group, they should be used with extreme caution and as a sole
agent. The benefits of therapy should be weighed against the risks. Above this age group, experience has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or
apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug [see Boxed
Warning and Contraindications (4)].
5.2 Use in Women of Childbearing Potential
Because of the risk to the fetus of neural tube defects and other major congenital malformations, which may
occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential
unless the drug is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
migraine). Women should use effective contraception while using valproate. Women who are planning a
pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy,
and alternative therapeutic options should be considered for these patients. [see Boxed Warning and Use in
Specific Populations (8.1)].
To prevent major seizures, Depakene should not be discontinued abruptly, as this can precipitate status
epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
pregnancy decreases the risk for congenital neural tube defects in the general population.
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5.3 Birth Defects and Neurobehavioral Adverse Effects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that
maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial
defects, cardiovascular malformations and malformations involving various body systems). The rate of
congenital malformations among babies born to mothers using valproate is about four times higher than the
rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that
folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk
for congenital neural tube defects in the general population.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
States and United Kingdom that found that children with prenatal exposure to valproate had lower
Differential Ability Scale (D.A.S) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal
exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98
104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94 - 104]). The D.A.S., which
has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years.
The D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo
IQ testing and generally correlates with IQ scores later in childhood.
Although all of the available studies have methodological limitations, the weight of the evidence supports
the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development.
In animal studies, valproate-exposed offspring had malformations similar to those seen in humans and
demonstrated behavioral deficits. [see Use in Specific Populations (8.1)]
5.4 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some
of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some
cases have occurred shortly after initial use as well as after several years of use. The rate based upon the
reported cases exceeds that expected in the general population and there have been cases in which pancreatitis
recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without
alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians
should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued.
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Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see
Boxed Warning].
5.5 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate
therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly
ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should
be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma,
encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained
mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and
lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of
UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or
symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while
receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy)
and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings and
Precautions (5.9)].
5.6 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored
for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in
mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after
starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials
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included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24
weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications
suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5
100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
Drug Patients
Relative Risk: Incidence of Events in
Risk Difference:
with Events Per
with Events Per
Drug Patients/Incidence in Placebo
Additional Drug
1000 Patients
1000 Patients
Patients
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical
trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and
psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed
are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and
behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider
whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
5.7 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may be dose-
related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients with epilepsy, 34/126
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patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x
109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to
normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the
probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110
mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses
should therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving
Depakene (valproic acid) be monitored for platelet count and coagulation parameters prior to planned surgery.
Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the
dosage or withdrawal of therapy.
5.8 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal
liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status,
hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and
Precautions (5.10)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate
interventions for treatment of hyperammonemia should be initiated, and such patients should undergo
investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions
(5.5, 5.8, 5.9)].
Asymptomatic elevations of ammonia are more common and when present, require close monitoring of
plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.
5.9 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or
without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of
hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive
function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see
Warnings and Precautions (5.10)]. In most cases, symptoms and signs abated with discontinuation of either
drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate
monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced
hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without
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encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing
defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy,
vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured [see Contraindications (4) and Warnings and Precautions (5.5, 5.8)].
5.10 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in
association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This
adverse reaction can also occur in patients using concomitant topiramate with valproate after starting
topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)].
Consideration should be given to stopping valproate in patients who develop hypothermia, which may be
manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant
alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical
management and assessment should include examination of blood ammonia levels.
5.11 Multi-organ Hypersensitivity Reaction
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation
of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days).
Although there have been a limited number of reports, many of these cases resulted in hospitalization and at
least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients
typically, although not exclusively, presented with fever and rash associated with other organ system
involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test
abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus,
nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected,
valproate should be discontinued and an alternative treatment started. Although the existence of cross
sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated
with multi-organ hypersensitivity would indicate this to be a possibility.
5.12 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may
reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum
valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative
antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop
significantly or seizure control deteriorates [see Drug Interactions (7.1)].
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5.13 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses
were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate
patients had somnolence compared to placebo, and although not statistically significant, there was a higher
proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than
with placebo. In some patients with somnolence (approximately one-half), there was associated reduced
nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients,
dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should
be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see
Dosage and Administration (2.2)].
5.14 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme induction,
periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the
early course of therapy [see Drug Interactions (7)].
5.15 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of
the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical significance of
these is unknown.
5.16 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under
certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of
these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy.
Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the
viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.
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6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may
not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium) tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote
was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was
the primary reason for discontinuation in the Depakote -treated patients (6%), compared to 1% of placebo-
treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote -treated patients
and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive
therapy for the treatment of complex partial seizures. Since patients were also treated with other antiepilepsy
drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to
Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive
Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
Placebo (%)
(n = 77)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
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Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose
Depakote group, and for which the incidence was greater than in the low dose group, in a controlled trial of
Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another
antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the
following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other
antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Depakote Monotherapy
for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
Low Dose (%)
(n = 131)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
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Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater
incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358
patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal
dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.
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6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic episodes
associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more
of patients from two placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine
headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two
placebo-controlled clinical trials of Depakote tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous
reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea, vomiting,
and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea,
abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased
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appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium
may result in reduction of gastrointestinal side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic
medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis,
"spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and Parkinsonism
have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate
alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has
developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following drug
withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in
patients with underlying urea cycle disorders [see Warnings and Precautions (5.5)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case
in a 6 month old infant taking valproate and several other concomitant medications. An additional case of
toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several
concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have
been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be
reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage
[see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis,
hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency,
bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be
dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes
in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and
Precautions (5.1)].
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Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.15)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not
been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.4)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and inappropriate ADH
secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent
nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of
women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of
glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine,
and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will
generally have longer half-lives and higher concentrations than patients receiving polytherapy with
antiepilepsy drugs.
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In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to
have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a
relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations
should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly prescribed
medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions
are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to
pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of valproate.
Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β
oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was
decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin.
Caution should be observed if valproate and aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving
carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may
result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid
concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or
anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure
control deteriorates [see Warnings and Precautions (5.12)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy
(n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL)
compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak
concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when
felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily
dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage
adjustment may be necessary when it is co-administered with rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox,
Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients
already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already
receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on
the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not
exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
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Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females)
who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a
34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate
and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate
and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be
considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E)
increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a history of
absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co
administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy
volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and
20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged
upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg
with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in
elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide
alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be
monitored for alterations in serum concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from
26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced
when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic
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epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See
lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID
for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life and a 30%
decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose
excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate
serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for
neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate
dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co
administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was
associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume
of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent
volume of distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of
valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added
to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is
unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic
relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted
in patients taking anticoagulants.
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Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by
38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently
administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered with
clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers
(n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers
(n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on
valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and
without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.5, 5.8, 5.9)].
Concomitant administration of topiramate with valproate has also been associated with hypothermia in
patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients
in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.8, 5.10)].
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should encourage pregnant
patients taking Depakene to enroll in the NAAED Pregnancy Registry. This can be done by calling toll free 1
888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at
the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other
adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication
increases the risk of congenital malformations, particularly neural tube defects, but also malformations
involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major
structural abnormalities is greatest during the first trimester; however, other serious developmental effects
can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born
to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than
the rate among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. [see Warnings and Precautions (5.3)].
In animal studies, offspring had structural malformations similar to those seen in humans and demonstrated
behavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal valproate
use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%,
compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in
10,000 births).
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• To prevent major seizures, women with epilepsy should not discontinue Depakene abruptly, as this can
precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor
seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the
drug may be considered prior to and during pregnancy in individual cases if the seizure disorder
severity and frequency do not pose a serious threat to the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered to
pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first trimester of
pregnancy decreases the risk for congenital neural tube defects in the general population. It is not
known whether the risk of neural tube defects in the offspring of women receiving valproate is
reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception
and during pregnancy should be routinely recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.7)]. A
patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth
to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in
pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also
been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of
neural tube defects and other structural abnormalities. Based on published data from the CDC’s National
Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%.
The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to
2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal
valproate exposure were reported among offspring of 149 enrolled women who used valproate during
pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial
defects, cardiovascular malformations and malformations of varying severity involving other body systems.
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The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% – 16.9%)
in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during
pregnancy (dose range 500 – 2000 mg/day). The major malformation rate among the internal comparison
group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy
was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following
exposure in utero to any other antiepileptic drug monotherapy.
Several published epidemiological studies have indicated that children exposed to valproate in utero have
lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United
States and United Kingdom that found that children with prenatal exposure to valproate had lower
Differential Ability Scale (D.A.S.) scores at age 3 (92 [95% C.I. 88-97]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (101 [95% C.I. 98
104]), carbamazepine (98 [95% C.I. 95-102]) and phenytoin (99 [95% C.I. 94-104]). The D.A.S., which has
a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children ages 2.5 to 17 years. The
D.A.S. is a measure of neurobehavioral development performed when children are too young to undergo IQ
testing and generally correlates with IQ scores later in childhood.
Although all of the available studies have methodological limitations, the weight of the evidence supports a
causal association between valproate exposure in utero and subsequent adverse effects on cognitive
development.
There are published case reports of fatal hepatic failure in offspring of women who used valproate during
pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal
structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment
of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body
surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac,
and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been
reported following valproate administration during critical periods of organogenesis, and the teratogenic
response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor,
and social interaction deficits) and brain histopathological changes have also been reported in mice and rat
offspring exposed prenatally to clinically relevant doses of valproate.
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8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing
woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk
of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning].
When Depakene is used in this patient group, it should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient
groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to
attain targeted total and unbound valproic acid concentrations. Pediatric patients (i.e., between 3 months and
10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of
10 years, children have pharmacokinetic parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid
concentrations. Interpretation of valproic acid concentrations in children should include consideration of
factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication
of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of Depakote in pediatric
patients were shown to be comparable to those in adults [see Adverse Reactions (6)].
Nonclinical Developmental Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal
dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated
during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was
less than the maximum recommended human dose on a mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania
associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65
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years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain,
somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether
these events indicate additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for
somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in these patients, and
dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage
and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been
reported; however, patients have recovered from valproate levels as high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem
hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or
emesis will vary with the time since ingestion. General supportive measures should be applied with particular
attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone
could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients
with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also known as
dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic
odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule contains 250
mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben, propylparaben,
and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose, water, and
natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate
exerts its antiepileptic effects have not been established. It has been suggested that its activity in epilepsy is
related to increased brain concentrations of gamma-aminobutyric acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented. One
contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the
clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the
bioactive valproate species.
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For example, because the plasma protein binding of valproate is concentration dependent, the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free
fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate, although some
patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules
deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may
vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or
postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food
or the capsule is taken intact), these differences should be of minor clinical importance under the steady state
conditions achieved in chronic use in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax could be
important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater
influence on the rate of absorption of the Depakote tablet (increase in Tmax from 4 to 8 hours) than on the
absorption of the Depakote sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with
dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be
affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in
primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability
(extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma
peak to trough concentrations between valproate formulations are inconsequential from a practical clinical
standpoint.
Co-administration of oral valproate products with food and substitution among the various Depakote and
Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see
Dosage and Administration (2.1)]. Nonetheless, any changes in dosage administration, or the addition or
discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status
and valproate plasma concentrations.
Reference ID: 3026475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 33 of 48
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction increases from
approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the
elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of
other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin,
carbamazepine, warfarin, and tolbutamide). (See Drug Interactions (7.2) for more detailed information on the
pharmacokinetic interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about
10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an
administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major
metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is
eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in
urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase
proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding.
The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2,
respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92
L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing
regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing
enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine,
phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate
Reference ID: 3026475
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Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 34 of 48
clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant
antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate valproate compared
to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of
glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased
volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-
life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children
greater than 2 months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e.,
mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that
approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be
reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free
fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and
Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and females (4.8
± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Reference ID: 3026475
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Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 35 of 48
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.3)]. Liver disease impairs the
capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7
patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that
study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with
decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate.
Accordingly, monitoring of total concentrations may be misleading since free concentrations may be
substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure
(creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by
about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein
binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum
recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the
incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend
for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for
humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects
in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats.
Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children
taking valproate, but this association was not observed in another study conducted in adults. There is some
evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an
increase in SCE frequency is not known.
Fertility
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FDA Approved Labeling Text dated October 7, 2011
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Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately
equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150
mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility
studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately
equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on
sperm production and fertility in humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur in isolation or
in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients
who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses
of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range"
were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo.
Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.
Table 5: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex
partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A
positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative
percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is
shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any
particular level of improvement was consistently higher for Depakote than for placebo. For example, 45% of
patients treated with Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of
patients treated with placebo.
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FDA Approved Labeling Text dated October 7, 2011
Page 37 of 48 Graphic of percent of patients on X axis, reduction in CPS rate on Y access
The second study assessed the capacity of Depakote to reduce the incidence of CPS when administered as the
sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose
treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they
continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with
adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized phase were then
brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an
interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In
patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy
were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-randomization
assessment.
Table 6: Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
Reference ID: 3026475
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FDA Approved Labeling Text dated October 7, 2011
Page 38 of 48
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex
partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive
percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent
reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is
shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients
achieving any particular level of reduction was consistently higher for high dose Depakote than for low dose
Depakote. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a reduction in
complex partial seizure rates compared to 54% of patients receiving low dose Depakote. % of patients on X access, percent reduction in CPS rate on Y access
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic acid, bearing
the trademark Depakene for product identification, in bottles of 100 capsules (NDC 0074-5681-13), and as a
red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of
16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
Reference ID: 3026475
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Page 39 of 48
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly
[see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and
Precautions (5.4)].
17.3 Birth Defects and Neurobehavioral Development Adverse Effects
Prescribers should inform pregnant women and women of childbearing potential that use of Depakene during
pregnancy increases the risk of birth defects and adverse effects on neurobehavioral development. Prescribers
should advise women to use effective contraception while using valproate. When appropriate, prescribers
should counsel these patients about alternative therapeutic options. This is particularly important when
valproate use is considered for a condition not usually associated with permanent injury or death (e.g.,
migraine). Patients should read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs
during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific
Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Patients, their caregivers, and families should be counseled that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal
thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to the
healthcare providers [see Warnings and Precautions (5.6)].
Reference ID: 3026475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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FDA Approved Labeling Text dated October 7, 2011
Page 40 of 48
17.5 Hyperammonemia
Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy and
be told to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.8, 5.9)].
17.6 CNS depression
Since valproate products may produce CNS depression, especially when combined with another CNS
depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an
automobile or operating dangerous machinery, until it is known that they do not become drowsy from the
drug.
17.7 Multi-organ Hypersensitivity Reaction
Patients should be instructed that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see
Warnings and Precautions (5.11)].
Reference ID: 3026475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get a refill.
There may be new information. This information does not take the place of talking to your healthcare provider
about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years old.
The risk of getting this serious liver damage is more likely to happen within the first 6 months of
treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
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o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your baby is at
risk for serious birth defects. The most common birth defects with Depakote or Depakene affect
the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur
in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These
defects can begin in the first month, even before you know you are pregnant. Other birth defects
can happen.
o Birth defects may occur even in children born to women who are not taking any medicines and
do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can lower the
chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your child is at
risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of birth defects.
o All women of child-bearing age should talk to their healthcare provider about using other
possible treatments instead of Depakote or Depakene. If the decision is made to use
Depakote or Depakene, you should use effective birth control (contraception) unless you
are planning to become pregnant.
o Tell your healthcare provider right away if you become pregnant while taking Depakote or
Depakene. You and your healthcare provider should decide if you will continue to take Depakote
or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk to your
healthcare provider about registering with the North American Antiepileptic Drug Pregnancy
Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry
is to collect information about the safety of antiepileptic drugs during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or actions in a
very small number of people, about 1 in 500.
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Page 43 of 48
Call a healthcare provider right away if you have any of these symptoms, especially if they are
new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping Depakote or
Depakene suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has
epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or
actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
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Page 44 of 48
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used alone or
with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in
Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in Depakote and
Depakene.
• have a genetic problem called urea cycle disorder
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your healthcare
provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and non
prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how well they
work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each
time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare provider
will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Reference ID: 3026475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 45 of 48
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush or chew
Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare provider if you can
not swallow Depakote or Depakene whole. You may need a different medicine.
• Depakote sprinkle capsules may be swallowed whole, or they may be opened and the contents may be
sprinkled on a small amount of soft food, such as applesauce or pudding. See the Patient Instructions
for Use at the end of this Medication Guide for detailed instructions on how to use Depakote Sprinkle
capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison Control
Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take other
medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you talk with your
doctor. Taking Depakote or Depakene with alcohol or drugs that cause sleepiness or dizziness may
make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or Depakene affect
you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 950F, feeling tired,
confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin blistering and
peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat,
trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less
than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your
doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 46 of 48
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information, ask your
healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800
FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
Depakote or Depakene for a condition for which it was not prescribed. Do not give Depakote or Depakene to
other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Depakote or Depakene. If you
would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare
provider for information about Depakote or Depakene that is written for health professionals.
For more information, go to www.rxabbott.com or call 1-800-633-9110.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 47 of 48
What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline
cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide,
and triacetin. The 500 mg tablets also contain iron oxide and polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch
(contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron
oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol,
sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
500 mg is Mfd. By Abbott Laboratories, North Chicago, IL 60064 U.S.A. or
Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
For Abbott Laboratories, North Chicago, IL 60064 U.S.A.
Depakote Tablets
Mfd. by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
Abbott Laboratories, North Chicago, IL 60064, U.S.A.Depakene Capsules
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018081/S-046/S-048/S-050/S-052
NDA 018082/S-031/S-033/S-035/S-037
Depakene (valproic acid) capsules and oral solution
FDA Approved Labeling Text dated October 7, 2011
Page 48 of 48
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by Abbott Laboratories, North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.
Issued 10/2011 Abbott Laboratories
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reference ID: 3026475
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:33.758983
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018081s046_18082s031lbl.pdf', 'application_number': 18082, 'submission_type': 'SUPPL ', 'submission_number': 33}
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11,150
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid) capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
•
Hepatotoxicity, including fatalities, usually during first 6 months
of treatment. Children under the age of two years and patients
with mitochondrial disorders are at higher risk. Monitor patients
closely, and perform serum liver testing prior to therapy and at
frequent intervals thereafter (5.1)
•
Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
•
Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depakene is an anti-epileptic drug indicated for:
•
Monotherapy and adjunctive therapy of complex partial seizures; sole
and adjunctive therapy of simple and complex absence seizures;
adjunctive therapy in patients with multiple seizure types that include
absence seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depakene is intended for oral administration. (2.1)
•
Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure
control or limiting side effects (2.1)
•
Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
-------DOSAGE FORMS AND STRENGTHS------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------CONTRAINDICATIONS------
•
Hepatic disease or significant hepatic dysfunction (4, 5.1)
•
Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
•
Suspected POLG-related disorder in children under two years of age (4,
5.1)
•
Known hypersensitivity to the drug (4, 5.12)
•
Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS------
•
Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
•
Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are
unacceptable; should not be administered to a woman of childbearing
potential unless essential (5.2, 5.3, 5.4)
•
Pancreatitis; Depakene should ordinarily be discontinued (5.5)
•
Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
•
Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
•
Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in
mental status (5.6, 5.9, 5.10)
•
Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
•
Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
•
Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS------
•
Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
•
The safety and tolerability of valproate in pediatric patients were shown
to be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS------
•
Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
•
Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations
is recommended (7.1)
•
Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by
inhibiting their metabolism or protein binding displacement (7.2)
•
Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
•
Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS------
•
Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
•
Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
•
Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: 07/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
Reference ID: 3349699
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2 Mania
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
* Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
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POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
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carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
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5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per 1000
Patients
Drug Patients with
Events Per 1000
Patients
Relative Risk: Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference: Additional
Drug Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
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during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients
with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at
least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment
discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts
normalized with continued treatment. In this study, the probability of thrombocytopenia
appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or
≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should
therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
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underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
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days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
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5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
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were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled
Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
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not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of
Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or
greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
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Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
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Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea,
vomiting, and indigestion. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia
with some weight loss and increased appetite with weight gain have also been reported. The
administration of delayed-release divalproex sodium may result in reduction of gastrointestinal
side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most
often in patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
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particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema
multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been
reported including a fatal case in a 6 month old infant taking valproate and several other
concomitant medications. An additional case of toxic epidermal necrosis resulting in death was
reported in a 35 year old patient with AIDS taking several concomitant medications and with a
history of multiple cutaneous drug reactions. Serious skin reactions have been reported with
concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and
behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis,
and frank hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and
appear to be dose-related. Occasionally, laboratory test results include increases in serum
bilirubin and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.5)].
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Metabolic: Hyperammonemia [see Warnings and Precautions (5.9)], hyponatremia, and
inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a
cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain,
cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and
hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
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The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
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Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
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amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
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concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
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In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
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7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
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Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially
important when valproate use is considered for a condition not usually associated
with permanent injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who
plan to become pregnant unless other treatments have failed to provide adequate
symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks. When
treating a pregnant woman or a woman of childbearing potential, carefully consider
both the potential risks and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
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• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
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104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
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Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
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8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
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For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
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dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
Reference ID: 3349699
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(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
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Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
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Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
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Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase Incidence
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Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
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15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
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Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
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Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
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Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with
Depakote or Depakene affect the brain and spinal cord and are called spina bifida or
neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to
mothers who use this medicine during pregnancy. These defects can begin in the first
month, even before you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy
can lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of
causing birth defects and decreased IQ in your child.
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
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o All women of child-bearing age should talk to their healthcare provider about
using other possible treatments instead of Depakote or Depakene. If the decision
is made to use Depakote or Depakene, you should use effective birth control
(contraception).
o Tell your healthcare provider right away if you become pregnant while taking
Depakote or Depakene. You and your healthcare provider should decide if you will
continue to take Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene,
talk to your healthcare provider about registering with the North American
Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1
888-233-2334. The purpose of this registry is to collect information about the safety
of antiepileptic drugs during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
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o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors,
thoughts, or feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
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Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
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• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
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• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
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Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
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dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote Sprinkle Capsules
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A816 July 2013
Reference ID: 3349699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:34.371403
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018081S056lbl.pdf', 'application_number': 18082, 'submission_type': 'SUPPL ', 'submission_number': 39}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid), capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
----------------------------INDICATIONS AND USAGE---------------------------
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence
seizures (1)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
----------------------DOSAGE FORMS AND STRENGTHS--------------------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------------------------------CONTRAINDICATIONS-----------------------------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
------------------------WARNINGS AND PRECAUTIONS----------------------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
• Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------------------------------ADVERSE REACTIONS-----------------------------
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------------------------------DRUG INTERACTIONS-----------------------------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
------------------------USE IN SPECIFIC POPULATIONS----------------------
• Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 8/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
5.8 Thrombocytopenia
1 INDICATIONS AND USAGE
5.9 Hyperammonemia
1.1 Epilepsy
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
1.2 Important Limitations
Topiramate Use
2 DOSAGE AND ADMINISTRATION
5.11 Hypothermia
2.1 Epilepsy
5.12 Multi-Organ Hypersensitivity Reactions
2.2 General Dosing Advice
5.13 Interaction with Carbapenem Antibiotics
3 DOSAGE FORMS AND STRENGTHS
5.14 Somnolence in the Elderly
4 CONTRAINDICATIONS
5.15 Monitoring: Drug Plasma Concentration
5 WARNINGS AND PRECAUTIONS
5.16 Effect on Ketone and Thyroid Function Tests
5.1 Hepatotoxicity
5.17 Effect on HIV and CMV Viruses Replication
5.2 Birth Defects
6 ADVERSE REACTIONS
5.3 Decreased IQ Following in utero Exposure
6.1 Epilepsy
5.4 Use in Women of Childbearing Potential
6.2 Mania
5.5 Pancreatitis
6.3 Migraine
5.6 Urea Cycle Disorders (UCD)
6.4 Post-Marketing Experience
5.7 Suicidal Behavior and Ideation
7 DRUG INTERACTIONS
Reference ID: 3613509
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3613509
dn2988v2-proposed-depakene-autism-2014-jul-23 2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
Reference ID: 3613509
dn2988v2-proposed-depakene-autism-2014-jul-23 3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
Reference ID: 3613509
dn2988v2-proposed-depakene-autism-2014-jul-23 4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25%
every 2 weeks. This reduction may be started at initiation of Depakene therapy, or delayed by 1
to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and
duration of withdrawal of the concomitant AED can be highly variable, and patients should be
monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
Reference ID: 3613509
dn2988v2-proposed-depakene-autism-2014-jul-23 5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
Reference ID: 3613509
dn2988v2-proposed-depakene-autism-2014-jul-23 6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
Reference ID: 3613509
dn2988v2-proposed-depakene-autism-2014-jul-23 7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
Reference ID: 3613509
dn2988v2-proposed-depakene-autism-2014-jul-23 8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
Reference ID: 3613509
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in
patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average,
had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had
treatment discontinued, with return of platelet counts to normal. In the remaining patients,
platelet counts normalized with continued treatment. In this study, the probability of
thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110
mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the
higher doses should therefore be weighed against the possibility of a greater incidence of adverse
effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
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with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
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5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
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Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
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Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
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Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
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Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience
The following adverse reactions have been identified during post approval use of Depakote.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens-
Johnson syndrome.
Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and
weakness.
Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia,
eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow
suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid
gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia,
hyperglycinemia, and inappropriate ADH secretion.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss.
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Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and
cutaneous vasculitis.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
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A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
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postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
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therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
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Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
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among babies born to epileptic mothers who used other anti-seizure monotherapies [see
Warnings and Precautions (5.3)].
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
An observational study has suggested that exposure to valproate products during pregnancy may
increase the risk of autism spectrum disorders. In this study, children born to mothers who had
used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]:
1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not
exposed to valproate products during pregnancy. The absolute risks for autism spectrum
disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI:
1.5%-1.6%) in children not exposed to valproate products. Because the study was observational
in nature, conclusions regarding a causal association between in utero valproate exposure and an
increased risk of autism spectrum disorder cannot be considered definitive.
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
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• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
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Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
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treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
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Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
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which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
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renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
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Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
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Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
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Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
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Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
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15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
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17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
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DEPAKOTE (dep-a-kOte)
(divalproex sodium delayed release capsules)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
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o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
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Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
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Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
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• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
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This label may not be the latest approved by FDA.
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General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-AXXX Month Year
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Depakote ER safely and effectively. See full prescribing information for
Depakote ER.
Depakote ER (divalproex sodium) Tablet, Extended Release for Oral use
Initial U.S. Approval: 2000
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Contraindications, Prophylaxis of Migraines in Pregnancy (4) 06/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
Warning and Precautions, Medication Residue in the Stool (5.18) 02/2013
-------INDICATIONS AND USAGE-------
Depakote ER is an anti-epileptic drug indicated for:
• Acute treatment of manic or mixed episodes associated with bipolar
disorder, with or without psychotic features (1.1)
• Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence seizures; adjunctive therapy in patients with
multiple seizure types that include absence seizures (1.2)
• Prophylaxis of migraine headaches (1.3)
-------DOSAGE AND ADMINISTRATION-------
• Depakote ER is intended for once-a-day oral administration. Depakote ER
should be swallowed whole and should not be crushed or chewed (2.1,
2.2).
• Mania: Initial dose is 25 mg/kg/day, increasing as rapidly as possible to
achieve therapeutic response or desired plasma level (2.1). The maximum
recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1
week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response;
if response is not satisfactory, check valproate plasma level; see full
prescribing information for conversion to monotherapy (2.2). The
maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by
5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The
maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Migraine: The recommended starting dose is 500 mg/day for 1 week,
thereafter increasing to 1000 mg/day (2.3).
-------DOSAGE FORMS AND STRENGTHS-------
Tablets: 250 mg and 500 mg (3)
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
• Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy or bipolar disorder if other
medications are unacceptable; should not be administered to a woman of
childbearing potential unless essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakote ER should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakote ER,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status, and also with concomitant topiramate use; consider discontinuation
of valproate therapy (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakote ER (5.12)
• Somnolence in the elderly can occur. Depakote ER dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) reported in adult studies
are nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain,
dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back
pain, alopecia, headache, fever, anorexia, constipation, diplopia,
amblyopia/blurred, ataxia, nystagmus, emotional lability, thinking
abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis,
ecchymosis, peripheral edema, insomnia, nervousness, depression,
pharyngitis, dyspnea, tinnitus (6.1, 6.2, 6.3, 6.4).
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
primidone, phenobarbital, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dose adjustment is indicated whenever enzyme-
inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations
are recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakote ER
(7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakote ER can cause congenital malformations including
neural tube defects and decreased IQ. (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1.1 Mania
1 INDICATIONS AND USAGE
1.2 Epilepsy
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1.3 Migraine
1.4 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Mania
2.2 Epilepsy
2.3 Migraine
2.4 Conversion from Depakote to Depakote ER
2.5 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
5.18 Medication Residue in the Stool
6 ADVERSE REACTIONS
6.1 Mania
6.2 Epilepsy
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Effect of Disease
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Mania
14.2 Epilepsy
14.3 Migraine
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-organ Hypersensitivity Reaction
17.8 Medication Residue in the Stool
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate and its derivatives. These incidents usually have occurred during the first six
months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In
patients with epilepsy, a loss of seizure control may also occur. Patients should be
monitored closely for appearance of these symptoms. Serum liver tests should be
performed prior to therapy and at frequent intervals thereafter, especially during the first
six months [see Warnings and Precautions (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakote ER is used in this
patient group, it should be used with extreme caution and as a sole agent. The benefits of
therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases
considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakote ER is contraindicated in patients known to
have mitochondrial disorders caused by POLG mutations and children under two years of
age who are clinically suspected of having a mitochondrial disorder [see Contraindications
(4)]. In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote ER should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakote ER for the development of acute liver injury with regular clinical assessments
and serum liver testing. POLG mutation screening should be performed in accordance
with current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate is therefore contraindicated in pregnant women treated for prophylaxis of
migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant
women with epilepsy or bipolar disorder if other medications have failed to control their
symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
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is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Mania
Depakote ER is a valproate and is indicated for the treatment of acute manic or mixed episodes
associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct
period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms
of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas,
grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is
characterized by the criteria for a manic episode in conjunction with those for a major depressive
episode (depressed mood, loss of interest or pleasure in nearly all activities).
The efficacy of Depakote ER is based in part on studies of Depakote (divalproex sodium delayed
release tablets) in this indication, and was confirmed in a 3-week trial with patients meeting
DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute
mania [see Clinical Studies (14.1)].
The effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been
demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use
Depakote ER for extended periods should continually reevaluate the long-term risk-benefits of
the drug for the individual patient.
1.2 Epilepsy
Depakote ER is indicated as monotherapy and adjunctive therapy in the treatment of adult
patients and pediatric patients down to the age of 10 years with complex partial seizures that
occur either in isolation or in association with other types of seizures. Depakote ER is also
indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence
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seizures in adults and children 10 years of age or older, and adjunctively in adults and children
10 years of age or older with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
1.3 Migraine
Depakote ER is indicated for prophylaxis of migraine headaches. There is no evidence that
Depakote ER is useful in the acute treatment of migraine headaches.
1.4 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
Depakote ER is contraindicated for prophylaxis of migraine headaches in women who are
pregnant.
2 DOSAGE AND ADMINISTRATION
Depakote ER is an extended-release product intended for once-a-day oral administration.
Depakote ER tablets should be swallowed whole and should not be crushed or chewed.
2.1 Mania
Depakote ER tablets are administered orally. The recommended initial dose is 25 mg/kg/day
given once daily. The dose should be increased as rapidly as possible to achieve the lowest
therapeutic dose which produces the desired clinical effect or the desired range of plasma
concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were
dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL.
The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer
term management of a patient who improves during Depakote ER treatment of an acute manic
episode. While it is generally agreed that pharmacological treatment beyond an acute response in
mania is desirable, both for maintenance of the initial response and for prevention of new manic
episodes, there are no data to support the benefits of Depakote ER in such longer-term treatment
(i.e., beyond 3 weeks).
2.2 Epilepsy
Depakote ER (divalproex sodium) extended release tablets are administered orally, and must be
swallowed whole. As Depakote ER dosage is titrated upward, concentrations of clonazepam,
diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or
phenytoin may be affected [see Drug Interactions (7.2)].
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Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote ER has not been systematically studied as initial therapy. Patients should initiate
therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to
achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses
below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels
should be measured to determine whether or not they are in the usually accepted therapeutic
range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses
above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25%
every 2 weeks. This reduction may be started at initiation of Depakote ER therapy, or delayed by
1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and
duration of withdrawal of the concomitant AED can be highly variable, and patients should be
monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote ER may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The
dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or
phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may
interact with these or other concurrently administered AEDs as well as other drugs, periodic
plasma concentration determinations of concomitant AEDs are recommended during the early
course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
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The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As Depakote ER dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
2.3 Migraine
Depakote ER is indicated for prophylaxis of migraine headaches in adults.
The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000
mg once daily. Although doses other than 1000 mg once daily of Depakote ER have not been
evaluated in patients with migraine, the effective dose range of Depakote (divalproex sodium
delayed-release tablets) in these patients is 500-1000 mg/day. As with other valproate products,
doses of Depakote ER should be individualized and dose adjustment may be necessary. If a
patient requires smaller dose adjustments than that available with Depakote ER, Depakote should
be used instead.
2.4 Conversion from Depakote to Depakote ER
In adult patients and pediatric patients 10 years of age or older with epilepsy previously
receiving Depakote, Depakote ER should be administered once-daily using a dose 8 to 20%
higher than the total daily dose of Depakote (Table 1). For patients whose Depakote total daily
dose cannot be directly converted to Depakote ER, consideration may be given at the clinician’s
discretion to increase the patient’s Depakote total daily dose to the next higher dosage before
converting to the appropriate total daily dose of Depakote ER.
Table 1. Dose Conversion
Depakote
Depakote ER
Total Daily Dose (mg)
(mg)
500* - 625
750
750* - 875
1000
1000*-1125
1250
1250-1375
1500
1500-1625
1750
1750
2000
1875-2000
2250
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2125-2250
2500
2375
2750
2500-2750
3000
2875
3250
3000-3125
3500
* These total daily doses of Depakote cannot be directly converted to an 8 to 20% higher total
daily dose of Depakote ER because the required dosing strengths of Depakote ER are not
available. Consideration may be given at the clinician's discretion to increase the patient's
Depakote total daily dose to the next higher dosage before converting to the appropriate total
daily dose of Depakote ER.
There is insufficient data to allow a conversion factor recommendation for patients with
DEPAKOTE doses above 3125 mg/day. Plasma valproate Cmin concentrations for DEPAKOTE
ER on average are equivalent to DEPAKOTE, but may vary across patients after conversion. If
satisfactory clinical response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL)
[see Clinical Pharmacology (12.2)].
2.5 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in
the elderly lower than 250 mg can only be achieved by the use of Depakote. Dosage should be
increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration,
somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should
be considered in patients with decreased food or fluid intake and in patients with excessive
somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability
and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5)
and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
Compliance
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Patients should be informed to take Depakote ER every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
3 DOSAGE FORMS AND STRENGTHS
Depakote ER 250 mg is available as white ovaloid tablets with the “a” logo and the code (HF).
Each Depakote ER tablet contains divalproex sodium equivalent to 250 mg of valproic acid.
Depakote ER 500 mg is available as gray ovaloid tablets with the “a” logo and the code HC.
Each Depakote ER tablet contains divalproex sodium equivalent to 500 mg of valproic acid.
4 CONTRAINDICATIONS
• Depakote ER should not be administered to patients with hepatic disease or significant
hepatic dysfunction [see Warnings and Precautions (5.1)].
• Depakote ER is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakote ER is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakote ER is contraindicated in patients with known urea cycle disorders [see Warnings
and Precautions (5.6)].
• Depakote ER is contraindicated for use in prophylaxis of migraine headaches in pregnant
women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
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those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakote ER is used in this patient group, it should be used with extreme caution and as a
sole agent. The benefits of therapy should be weighed against the risks. In progressively older
patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity
decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakote ER is contraindicated in patients known to have mitochondrial disorders caused by
POLG mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote ER should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakote ER for
the development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
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5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]),
carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of
migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to
become pregnant should not be treated with valproate unless other treatments have failed to
provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
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5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, Depakote ER should ordinarily
be discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders
Depakote ER is contraindicated in patients with known urea cycle disorders (UCD).
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
Depakote ER therapy, evaluation for UCD should be considered in the following patients: 1)
those with a history of unexplained encephalopathy or coma, encephalopathy associated with a
protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation,
or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and
lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a
family history of UCD or a family history of unexplained infant deaths (particularly males); 4)
those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakote ER, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
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The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo
Patients with
Events Per
1000 Patients
Drug Patients
with Events
Per 1000
Patients
Relative Risk: Incidence of
Events in Drug
Patients/Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients with Events
Per 1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakote ER or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy,
34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value
of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with
return of platelet counts to normal. In the remaining patients, platelet counts normalized with
continued treatment. In this study, the probability of thrombocytopenia appeared to increase
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significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL
(males). The therapeutic benefit which may accompany the higher doses should therefore be
weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakote ER be monitored for platelet count and
coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder
of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
During the placebo controlled pediatric mania trial, one (1) in twenty (20) adolescents (5%)
treated with valproate developed increased plasma ammonia levels compared to no (0) patients
treated with placebo.
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not
due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
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5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
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nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.4)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
5.18 Medication Residue in the Stool
There have been rare reports of medication residue in the stool. Some patients have had anatomic
(including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI
transit times. In some reports, medication residues have occurred in the context of diarrhea. It is
recommended that plasma valproate levels be checked in patients who experience medication
residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated,
alternative treatment may be considered.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
Information on pediatric adverse reactions is presented in section 8.
6.1 Mania
The incidence of treatment-emergent events has been ascertained based on combined data from
two three week placebo-controlled clinical trials of Depakote ER in the treatment of manic
episodes associated with bipolar disorder.
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Table 3 summarizes those adverse reactions reported for patients in these trials where the
incidence rate in the Depakote ER-treated group was greater than 5% and greater than the
placebo incidence.
Table 3. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During
Placebo-Controlled Trials of Acute Mania1
Adverse Event
Depakote ER
(n=338)
Placebo
(n=263)
Somnolence
26%
14%
Dyspepsia
23%
11%
Nausea
19%
13%
Vomiting
13%
5%
Diarrhea
12%
8%
Dizziness
12%
7%
Pain
11%
10%
Abdominal pain
10%
5%
Accidental injury
6%
5%
Asthenia
6%
5%
Pharyngitis
6%
5%
1. The following adverse reactions/event occurred at an equal or greater incidence for placebo
than for Depakote ER: headache
The following additional adverse reactions were reported by greater than 1% but not more than
5% of the Depakote ER-treated patients in controlled clinical trials:
Body as a Whole: Back Pain, Flu Syndrome, Infection, Infection Fungal
Cardiovascular System: Hypertension
Digestive System: Constipation, Dry Mouth, Flatulence
Hemic and Lymphatic System: Ecchymosis
Metabolic and Nutritional Disorders: Peripheral Edema
Musculoskeletal System: Myalgia
Nervous System: Abnormal Gait, Hypertonia, Tremor
Respiratory System: Rhinitis
Skin and Appendages: Pruritus, Rash
Special Senses: Conjunctivitis
Urogenital System: Urinary Tract Infection, Vaginitis
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6.2 Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in the
placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to
determine whether the following adverse reactions can be ascribed to Depakote alone, or the
combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients Treated with Valproate During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Event
Depakote (%)
(N=77)
Placebo (%)
(N=70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
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Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 5 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose valproate group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
Table 5. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1
Body System/Event
High Dose (%)
(n=131)
Low Dose (%)
(n=134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
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Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1. Headache was the only adverse event that occurred in ≥5% of patients in the high dose group
and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.3 Migraine
Based on two placebo-controlled clinical trials and their long term extension, valproate was
generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the
202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for
intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term
extension study, the adverse reactions reported as the primary reason for discontinuation by ≥
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1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight
gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression
(1%).
Table 6 includes those adverse reactions reported for patients in the placebo-controlled trial
where the incidence rate in the Depakote ER-treated group was greater than 5% and was greater
than that for placebo patients.
Table 6. Adverse Reactions Reported by >5% of Depakote ER-Treated Patients During the
Migraine Placebo-Controlled Trial with a Greater Incidence than Patients Taking Placebo1
Body System
Event
Depakote ER
(n=122)
Placebo
(n=115)
Gastrointestinal System
Nausea
15%
9%
Dyspepsia
7%
4%
Diarrhea
7%
3%
Vomiting
7%
2%
Abdominal Pain
7%
5%
Nervous System
Somnolence
7%
2%
Other
Infection
15%
14%
1. The following adverse reactions occurred in greater than 5% of Depakote ER-treated patients
and at a greater incidence for placebo than for Depakote ER: asthenia and flu syndrome.
The following additional adverse reactions were reported by greater than 1% but not more than
5% of Depakote ER-treated patients and with a greater incidence than placebo in the placebo-
controlled clinical trial for migraine prophylaxis:
Body as a Whole: Accidental injury, viral infection.
Digestive System: Increased appetite, tooth disorder.
Metabolic and Nutritional Disorders: Edema, weight gain.
Nervous System: Abnormal gait, dizziness, hypertonia, insomnia, nervousness, tremor, vertigo.
Respiratory System: Pharyngitis, rhinitis.
Skin and Appendages: Rash.
Special Senses: Tinnitus.
Table 7 includes those adverse reactions reported for patients in the placebo-controlled trials
where the incidence rate in the valproate-treated group was greater than 5% and was greater than
that for placebo patients.
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Table 7. Adverse Reactions Reported by > 5% of Valproate-Treated Patients During
Migraine Placebo-Controlled Trials with a Greater Incidence than Patients Taking
Placebo1
Body System
Reaction
Depakote
(n=202)
Placebo
(n=81)
Gastrointestinal System
Nausea
31%
10%
Dyspepsia
13%
9%
Diarrhea
12%
7%
Vomiting
11%
1%
Abdominal pain
9%
4%
Increased appetite
6%
4%
Nervous System
Asthenia
20%
9%
Somnolence
17%
5%
Dizziness
12%
6%
Tremor
9%
0%
Other
Weight gain
8%
2%
Back pain
8%
6%
Alopecia
7%
1%
1. The following adverse reactions occurred in greater than 5% of Depakote-treated patients and
at a greater incidence for placebo than for Depakote: flu syndrome and pharyngitis.
The following additional adverse reactions were reported by greater than 1% but not more than
5% of the 202 valproate-treated patients in the controlled clinical trials:
Body as a Whole: Chest pain.
Cardiovascular System: Vasodilatation.
Digestive System: Constipation, dry mouth, flatulence, and stomatitis.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Peripheral edema.
Musculoskeletal System: Leg cramps.
Nervous System: Abnormal dreams, confusion, paresthesia, speech disorder, and thinking
abnormalities.
Respiratory System: Dyspnea, and sinusitis.
Skin and Appendages: Pruritus.
Urogenital System: Metrorrhagia.
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6.4 Other Patient Populations
Mania
The following adverse reactions not listed previously were reported by greater than 1% of
Depakote-treated patients and with a greater incidence than placebo in placebo-controlled trials
of manic episodes associated with bipolar disorder:
Body as a Whole: Chills, chills and fever, drug level increased, neck rigidity.
Cardiovascular System: Arrhythmia, hypotension, postural hypotension.
Digestive System: Dysphagia, fecal incontinence, gastroenteritis, glossitis, gum hemorrhage,
mouth ulceration.
Hemic and Lymphatic System: Anemia, bleeding time increased, leucopenia.
Metabolic and Nutritional Disorders: Hypoproteinemia.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, dysarthria, hallucinations, hypokinesia,
psychosis, reflexes increased, sleep disorder, tardive dyskinesia.
Respiratory System: Hiccup.
Skin and Appendages: Discoid lupus erythematosus, erythema nodosum, furunculosis,
maculopapular rash, seborrhea, sweating, vesiculobullous rash.
Special Senses: Conjunctivitis, dry eyes, eye disorder, eye pain, photophobia, taste perversion.
Urogenital System: Cystitis, menstrual disorder.
Epilepsy
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal
The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and
indigestion. These effects are usually transient and rarely require discontinuation of therapy.
Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some
weight loss and increased appetite with weight gain have also been reported. The administration
of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in
some patients.
CNS Effects
Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
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the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic
Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported
including a fatal case in a 6 month old infant taking valproate and several other concomitant
medications. An additional case of toxic epidermal necrosis resulting in death was reported in a
35 year old patient with AIDS taking several concomitant medications and with a history of
multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant
administration of lamotrigine and valproate [see Drug Interactions (7.2)].
Psychiatric
Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal
Weakness.
Hematologic
Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected
in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank
hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic
Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to
be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and
abnormal changes in other liver function tests. These results may reflect potentially serious
hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine
Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic
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Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].
Metabolic
Hyperammonemia [see Warnings and Precautions (5.9, 5.10)], hyponatremia, and inappropriate
ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary
Enuresis and urinary tract infection.
Special Senses
Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other
Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia
[see Warnings and Precautions (5.11)].
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
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The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Whether or not the interaction observed in this
study applies to adults is unknown, but caution should be observed if valproate and aspirin are to
be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
in not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
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A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronosyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
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Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by
a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance
as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially
along with other anticonvulsants, should be monitored for alterations in serum concentrations of
both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase
in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The
fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
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In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n=11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder
[see Warnings and Precautions (5.2, 5.3)].
Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakote, physicians should
encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must
be done by the patients themselves. Information on the registry can be found at the website,
http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
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• Valproate is contraindicated during pregnancy in women being treated for prophylaxis of
migraine headaches.
• Valproate should not be used to treat women with epilepsy or bipolar disorder who are
pregnant or who plan to become pregnant unless other treatments have failed to provide
adequate symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks. When treating a
pregnant woman or a woman of childbearing potential, carefully consider both the
potential risks and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
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mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I.
104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in
this patient group, it should be used with extreme caution and as a sole agent. The benefits of
therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
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indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older
patient groups.
Younger children, especially those receiving enzyme inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentration. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were
shown to be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was
occasionally associated with the latter two events. It is not clear whether these events indicate
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additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.5)].
There is insufficient information available to discern the safety and effectiveness of valproate for
the prophylaxis of migraines in patients over 65.
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26 years) [see Clinical
Pharmacology (12.3)].
8.6 Effect of Disease
Liver Disease
[(See Boxed Warning, Contraindications (4), Warnings and Precautions (5), and Clinical
Pharmacology (12.3)]. Liver disease impairs the capacity to eliminate valproate.
10 OVERDOSAGE
Over dosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and
valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic
acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen
bis(2-propylpentanoate). Divalproex sodium has the following structure:
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Divalproex sodium occurs as a white powder with a characteristic odor.
Depakote ER 250 and 500 mg tablets are for oral administration. Depakote ER tablets contain
divalproex sodium in a once-a-day extended-release formulation equivalent to 250 and 500 mg
of valproic acid.
Inactive Ingredients
Depakote ER 250 and 500 mg tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin.
In addition, 500 mg tablets contain iron oxide and polydextrose.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms
by which valproate exerts its therapeutic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate may not
provide a reliable index of the bioactive valproate species.
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For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total
valproate, although some patients may be controlled with lower or higher plasma concentrations.
Mania
In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with
trough plasma concentrations between 85 and 125 mcg/mL [see Dosage and Administration
(2.1)].
12.3 Pharmacokinetics
Absorption/Bioavailability
The absolute bioavailability of Depakote ER tablets administered as a single dose after a meal
was approximately 90% relative to intravenous infusion.
When given in equal total daily doses, the bioavailability of Depakote ER is less than that of
Depakote (divalproex sodium delayed-release tablets). In five multiple-dose studies in healthy
subjects (N=82) and in subjects with epilepsy (N=86), when administered under fasting and
nonfasting conditions, Depakote ER given once daily produced an average bioavailability of
89% relative to an equal total daily dose of Depakote given BID, TID, or QID. The median time
to maximum plasma valproate concentrations (Cmax) after Depakote ER administration ranged
from 4 to 17 hours. After multiple once-daily dosing of Depakote ER, the peak-to-trough
fluctuation in plasma valproate concentrations was 10-20% lower than that of regular Depakote
given BID, TID, or QID.
Conversion from Depakote to Depakote ER
When Depakote ER is given in doses 8 to 20% higher than the total daily dose of Depakote, the
two formulations are bioequivalent. In two randomized, crossover studies, multiple daily doses
of Depakote were compared to 8 to 20% higher once-daily doses of Depakote ER. In these two
studies, Depakote ER and Depakote regimens were equivalent with respect to area under the
curve (AUC; a measure of the extent of bioavailability). Additionally, valproate Cmax was lower,
and Cmin was either higher or not different, for Depakote ER relative to Depakote regimens (see
Table 9).
Table 9. Bioavailability of Depakote ER Tablets Relative to Depakote When Depakote ER
Dose is 8 to 20% Higher
Study Population
Regimens
Relative Bioavailability
Depakote ER vs.
Depakote
AUC24
Cmax
Cmin
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Healthy Volunteers
(N=35)
1000 & 1500 mg
Depakote ER vs.
875 & 1250 mg
Depakote
1.059
0.882
1.173
Patients with
epilepsy on
concomitant enzyme-
inducing antiepilepsy
drugs (N = 64)
1000 to 5000 mg
Depakote ER vs.
875 to 4250 mg
Depakote
1.008
0.899
1.022
Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and
lamotrigine were evaluated) that induce the cytochrome P450 isozyme system did not
significantly alter valproate bioavailability when converting between Depakote and Depakote
ER.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide)
[see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions
of valproate with other drugs].
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
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The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Pediatric
The valproate pharmacokinetic profile following administration of Depakote ER was
characterized in a multiple-dose, non-fasting, open label, multi-center study in children and
adolescents. Depakote ER once daily doses ranged from 250-1750 mg. Once daily administration
of Depakote ER in pediatric patients (10-17 years) produced plasma VPA concentration-time
profiles similar to those that have been observed in adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.4)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free
valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute
hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and
larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed
Warning, Contraindications (4), and Warnings and Precautions (5.1)].
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
14.1 Mania
The effectiveness of Depakote ER for the treatment of acute mania is based in part on studies
establishing the effectiveness of Depakote (divalproex sodium delayed release tablets) for this
indication. Depakote ER’s effectiveness was confirmed in one randomized, double-blind,
placebo-controlled, parallel group, 3-week, multicenter study. The study was designed to
evaluate the safety and efficacy of Depakote ER in the treatment of bipolar I disorder, manic or
mixed type, in adults. Adult male and female patients who had a current DSM-IV TR primary
diagnosis of bipolar I disorder, manic or mixed type, and who were hospitalized for acute mania,
were enrolled into this study. Depakote ER was initiated at a dose of 25 mg/kg/day given once
daily, increased by 500 mg/day on Day 3, then adjusted to achieve plasma valproate
concentrations in the range of 85-125 mcg/mL. Mean daily Depakote ER doses for observed
cases were 2362 mg (range: 500-4000), 2874 mg (range: 1500-4500), 2993 mg (range: 1500
4500), 3181 mg (range: 1500-5000), and 3353 mg (range: 1500-5500) at Days 1, 5, 10, 15, and
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21, respectively. Mean valproate concentrations were 96.5 mcg/mL, 102.1 mcg/mL, 98.5
mcg/mL, 89.5 mcg/mL at Days 5, 10, 15 and 21, respectively. Patients were assessed on the
Mania Rating Scale (MRS; score ranges from 0-52).
Depakote ER was significantly more effective than placebo in reduction of the MRS total score.
14.2 Epilepsy
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design, (adjunctive therapy)
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 10. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on
Treatment
Number
of Patients
Baseline
Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for valproate than placebo at
p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for valproate than for placebo. For example, 45% of patients treated with
valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of valproate to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to valproate. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 11. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number
of Patients
Baseline
Incidence
Randomized
Phase Incidence
High dose Valproate
131
13.2
10.7*
Low dose Valproate
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose valproate than for low dose valproate.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
valproate.
Figure 2
Information on pediatric studies are presented in section 8.
14.3 Migraine
The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group
clinical trial demonstrated the effectiveness of Depakote ER in the prophylactic treatment of
migraine headache. This trial recruited patients with a history of migraine headaches with or
without aura occurring on average twice or more a month for the preceding three months.
Patients with cluster or chronic daily headaches were excluded. Women of childbearing potential
were allowed in the trial if they were deemed to be practicing an effective method of
contraception.
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Patients who experienced ≥ 2 migraine headaches in the 4-week baseline period were
randomized in a 1:1 ratio to Depakote ER or placebo and treated for 12 weeks. Patients initiated
treatment on 500 mg once daily for one week, and were then increased to 1000 mg once daily
with an option to permanently decrease the dose back to 500 mg once daily during the second
week of treatment if intolerance occurred. Ninety-eight of 114 Depakote ER-treated patients
(86%) and 100 of 110 placebo-treated patients (91%) treated at least two weeks maintained the
1000 mg once daily dose for the duration of their treatment periods. Treatment outcome was
assessed on the basis of reduction in 4-week migraine headache rate in the treatment period
compared to the baseline period.
Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with Depakote ER
(N=122) or placebo (N=115). Four patients were below the age of 18 and 3 were above the age
of 65. Two hundred and two patients (101 in each treatment group) completed the treatment
period. The mean reduction in 4-week migraine headache rate was 1.2 from a baseline mean of
4.4 in the Depakote ER group, versus 0.6 from a baseline mean of 4.2 in the placebo group. The
treatment difference was statistically significant (see Figure 3).
Figure 3 Mean Reduction In 4-Week Migraine Headache Rates
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
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16 HOW SUPPLIED/STORAGE AND HANDLING
Depakote ER 250 mg is available as white ovaloid tablets with the “a” logo and the code (HF).
Each Depakote ER tablet contains divalproex sodium equivalent to 250 mg of valproic acid in
the following package sizes:
Bottles of 60....……………………………………………(NDC 0074-3826-60).
Bottles of 100……………………………………………..(NDC 0074-3826-13).
Bottles of 500……………………………………………..(NDC 0074-3826-53).
Unit Dose Packages of 100..................…………………..(NDC 0074-3826-11).
Depakote ER 500 mg is available as gray ovaloid tablets with the “a” logo and the code HC.
Each Depakote ER tablet contains divalproex sodium equivalent to 500 mg of valproic acid in
the following packaging sizes:
Bottles of 100...................................................................(NDC 0074-7126-13).
Bottles of 500...................................................................(NDC 0074-7126-53).
Unit Dose Packages of 100...............................................(NDC 0074-7126-11).
Recommended Storage
Store tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
Room Temperature].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
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patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakote ER, may increase
the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-organ Hypersensitivity Reaction
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
17.8 Medication Residue in the Stool
Instruct patients to notify their healthcare provider if they notice a medication residue in the stool
[see Warnings and Precautions (5.18)].
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
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MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old. The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
• If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
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this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
• Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
• Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
• If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
• There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
• Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
• All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
• Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
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o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that do not stop (status
epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
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What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 950F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering
and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips,
tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A916 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid) capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence
seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
-------DOSAGE FORMS AND STRENGTHS-------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1) Suspected POLG-related disorder in
children under two years of age (4, 5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
• Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
Reference ID: 3520933
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
Reference ID: 3520933
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death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
Reference ID: 3520933
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Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
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5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients
with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at
least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment
discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts
normalized with continued treatment. In this study, the probability of thrombocytopenia
appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or
≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should
therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
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mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
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higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
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Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
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Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
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Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
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Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea,
vomiting, and indigestion. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia
with some weight loss and increased appetite with weight gain have also been reported. The
administration of delayed-release divalproex sodium may result in reduction of gastrointestinal
side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most
often in patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema
multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been
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reported including a fatal case in a 6 month old infant taking valproate and several other
concomitant medications. An additional case of toxic epidermal necrosis resulting in death was
reported in a 35 year old patient with AIDS taking several concomitant medications and with a
history of multiple cutaneous drug reactions. Serious skin reactions have been reported with
concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and
behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis,
and frank hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and
appear to be dose-related. Occasionally, laboratory test results include increases in serum
bilirubin and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.5)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.9)], hyponatremia, and
inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a
cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain,
cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and
hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
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7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
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Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
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Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
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Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
Reference ID: 3520933
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In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
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Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
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social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
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In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
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The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
Reference ID: 3520933
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o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote Tablets
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A914 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Depakote safely and effectively. See full prescribing information for
Depakote.
Depakote Sprinkle Capsules (divalproex sodium coated particles in
capsules), for oral use
Initial U.S. Approval: 1989
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 06/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
Warnings and Precautions, Medication Residue in the Stool (5.18) 02/2013
-------INDICATIONS AND USAGE-------
Depakote is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence seizures; adjunctive therapy in patients with
multiple seizure types that include absence seizures (1)
-------DOSAGE AND ADMINISTRATION-------
• Depakote Sprinkle Capsules may be swallowed whole or the contents may
be sprinkled on soft food. The drug/food mixture should be swallowed
immediately (avoid chewing) (2.2)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1
week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response;
if response is not satisfactory, check valproate plasma level; see full
prescribing information for conversion to monotherapy (2.1)
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by
5 to 10 mg/kg/day until seizure control or limiting side effects (2.1)
-------DOSAGE FORMS AND STRENGTHS-------
Capsules: 125 mg (3)
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakote Sprinkle Capsules should ordinarily be
discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakote,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakote Sprinkle
Capsules (5.12)
• Somnolence in the elderly can occur. Depakote Sprinkle Capsules dosage
should be increased slowly and with regular monitoring for fluid and
nutritional intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) are thrombocytopenia,
nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain,
dyspepsia, diarrhea, increased appetite, tremor, weight gain, weight loss,
alopecia, headache, fever, anorexia, constipation, diplopia,
amblyopia/blurred vision, ataxia, nystagmus, emotional lability, thinking
abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis,
ecchymosis, peripheral edema, insomnia, nervousness, depression,
pharyngitis, dyspnea, tinnitus (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakote
Sprinkle Capsules (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakote Sprinkle Capsules can cause congenital
malformations including neural tube defects and decreased IQ (5.2, 5.3,
8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
2.2 General Dosing Advice
1 INDICATIONS AND USAGE
3 DOSAGE FORMS AND STRENGTHS
1.1 Epilepsy
4 CONTRAINDICATIONS
1.2 Important Limitations
5 WARNINGS AND PRECAUTIONS
2 DOSAGE AND ADMINISTRATION
5.1 Hepatotoxicity
2.1 Epilepsy
5.2 Birth Defects
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5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
5.18 Medication Residue in the Stool
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Effect of Disease
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
17.8 Medication Residue in the Stool
17.9 Administration Guide
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate and its derivatives. These incidents usually have occurred during the first six
months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In
patients with epilepsy, a loss of seizure control may also occur. Patients should be
monitored closely for appearance of these symptoms. Serum liver tests should be
performed prior to therapy and at frequent intervals thereafter, especially during the first
six months [see Warnings and Precautions (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakote Sprinkle Capsules are
used in this patient group, they should be used with extreme caution and as a sole agent.
The benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakote Sprinkle Capsules is contraindicated in patients
known to have mitochondrial disorders caused by POLG mutations and children under
two years of age who are clinically suspected of having a mitochondrial disorder [see
Contraindications (4)]. In patients over two years of age who are clinically suspected of
having a hereditary mitochondrial disease, Depakote Sprinkle Capsules should only be
used after other anticonvulsants have failed. This older group of patients should be closely
monitored during treatment with Depakote Sprinkle Capsules for the development of acute
liver injury with regular clinical assessments and serum liver testing. POLG mutation
screening should be performed in accordance with current clinical practice [see Warnings
and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
Reference ID: 3520933
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valproate use is considered for a condition not usually associated with permanent injury or
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakote Sprinkle Capsules are indicated as monotherapy and adjunctive therapy in the
treatment of adult patients and pediatric patients down to the age of 10 years with complex
partial seizures that occur either in isolation or in association with other types of seizures.
Depakote Sprinkle Capsules are also indicated for use as sole and adjunctive therapy in the
treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakote Sprinkle Capsules are administered orally. As Depakote dosage is titrated upward,
concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital,
carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
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Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote Sprinkle Capsules has not been systematically studied as initial therapy. Patients
should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25%
every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1
to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and
duration of withdrawal of the concomitant AED can be highly variable, and patients should be
monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote Sprinkle Capsules may be added to the patient's regimen at a dosage of 10 to 15
mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical
response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If
satisfactory clinical response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).
No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can
be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or
phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact
with these or other concurrently administered AEDs as well as other drugs, periodic plasma
concentration determinations of concomitant AEDs are recommended during the early course of
therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
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The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentrations for most patients with
absence seizures are considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakote Sprinkle Capsules dosage is titrated upward, blood concentrations of
phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote Sprinkle
Capsules should be initiated at the same daily dose and dosing schedule. After the patient is
stabilized on Depakote Sprinkle Capsules, a dosing schedule of two or three times a day may be
elected in selected patients.
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
Administration of Sprinkle Capsules
Depakote Sprinkle Capsules may be swallowed whole or may be administered by carefully
opening the capsule and sprinkling the entire contents on a small amount (teaspoonful) of soft
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food such as applesauce or pudding. The drug/food mixture should be swallowed immediately
(avoid chewing) and not stored for future use. Each capsule is oversized to allow ease of
opening.
3 DOSAGE FORMS AND STRENGTHS
Depakote Sprinkle Capsules are for oral administration. Depakote Sprinkle Capsules contain
specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid in a hard
gelatin capsule.
4 CONTRAINDICATIONS
• Depakote Sprinkle Capsules should not be administered to patients with hepatic disease or
significant hepatic dysfunction [see Warnings and Precautions (5.1)].
• Depakote Sprinkle Capsules is contraindicated in patients known to have mitochondrial
disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-
Huttenlocher Syndrome) and children under two years of age who are suspected of having a
POLG-related disorder [see Warnings and Precautions (5.1)].
• Depakote Sprinkle Capsules is contraindicated in patients with known hypersensitivity to the
drug [see Warnings and Precautions (5.12)].
• Depakote Sprinkle Capsules is contraindicated in patients with known urea cycle disorders
[see Warnings and Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
Reference ID: 3520933
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When Depakote is used in this patient group, it should be used with extreme caution and as a
sole agent. The benefits of therapy should be weighed against the risks. In progressively older
patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity
decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakote Sprinkle Capsules is contraindicated in patients known to have mitochondrial disorders
caused by POLG mutations and children under two years of age who are clinically suspected of
having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver
failure and liver-related deaths have been reported in patients with hereditary neurometabolic
syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g.,
Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote Sprinkle Capsules should only be used after other
anticonvulsants have failed. This older group of patients should be closely monitored during
treatment with Depakote Sprinkle Capsules for the development of acute liver injury with regular
clinical assessments and serum liver test monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
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scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]),
carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in
2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be
warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis
that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily
be discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders
Depakote is contraindicated in patients with known urea cycle disorders (UCD).
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakote, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
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The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo
Drug Patients Relative Risk: Incidence of
Risk Difference:
Patients with with Events
Events in Drug
Additional Drug
Events Per
Per 1,000
Patients/Incidence in
Patients with Events
1,000 Patients
Patients
Placebo Patients
Per 1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakote or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy,
34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value
of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with
return of platelet counts to normal. In the remaining patients, platelet counts normalized with
continued treatment. In this study, the probability of thrombocytopenia appeared to increase
significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL
(males). The therapeutic benefit which may accompany the higher doses should therefore be
weighed against the possibility of a greater incidence of adverse effects.
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Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakote be monitored for platelet count and coagulation
parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of
hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured [see Contraindications (4) and Warnings and Precautions
(5.6, 5.10)]. Hyperammonemia should also be considered in patients who present with
hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy
should be discontinued. Appropriate interventions for treatment of hyperammonemia should be
initiated, and such patients should undergo investigation for underlying urea cycle disorders [see
Contraindications (4) and Warnings and Precautions (5.6, 5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not
due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
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organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
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5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown [see Adverse Reactions (6.2)].
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
5.18 Medication Residue in the Stool
There have been rare reports of medication residue in the stool. Some patients have had anatomic
(including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI
transit times. In some reports, medication residues have occurred in the context of diarrhea. It is
recommended that plasma valproate levels be checked in patients who experience medication
residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated,
alternative treatment may be considered.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Hepatic failure (5.1)
Birth defects (5.2)
Decreased IQ following in utero exposure (5.3)
Pancreatitis (5.5)
Hyperammonemic encephalopathy (5.6, 5.9)
Thrombocytopenia (5.8)
Multi-organ hypersensitivity reactions (5.12)
Somnolence in the elderly (5.14)
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
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6.1 Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
In a long term (12-month) safety study in pediatric patients (n=169) between the ages of 3 and 10
years old, no clinically meaningful differences in the adverse event profile were observed when
compared to adults.
Table 2 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in the
placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to
determine whether the following adverse reactions can be ascribed to Depakote alone, or the
combination of Depakote and other antiepilepsy drugs.
Table 2. Adverse Reactions Reported by ≥ 5% of Patients Treated with Valproate During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Event
Depakote (%)
Placebo (%)
(n = 77)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
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Table 2. Adverse Reactions Reported by ≥ 5% of Patients Treated with Valproate During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose valproate group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Valproate Monotherapy for Complex Partial Seizuresa
Body System/Event
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
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Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
a. Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group
and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
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6.2 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal
The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and
indigestion. These effects are usually transient and rarely require discontinuation of therapy.
Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some
weight loss and increased appetite with weight gain have also been reported. The administration
of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in
some patients.
CNS Effects
Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic
Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported
including a fatal case in a 6 month old infant taking valproate and several other concomitant
medications. An additional case of toxic epidermal necrosis resulting in death was reported in a
35 year old patient with AIDS taking several concomitant medications and with a history of
multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant
administration of lamotrigine and valproate [see Drug Interactions (7.2)].
Psychiatric
Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal
Weakness.
Hematologic
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Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected
in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank
hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic
Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to
be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and
abnormal changes in other liver function tests. These results may reflect potentially serious
hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine
Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic
Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].
Metabolic
Hyperammonemia [see Warnings and Precautions (5.9, 5.10)], hyponatremia, and inappropriate
ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in
children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary
Enuresis and urinary tract infection.
Special Senses
Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other
Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia
[see Warnings and Precautions (5.11)].
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
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7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
in not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients
with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronosyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
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Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by
a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance
as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially
along with other anticonvulsants, should be monitored for alterations in serum concentrations of
both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase
in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The
fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
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Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n=11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
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No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9,5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakote, physicians should
encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must
be done by the patients themselves. Information on the registry can be found at the website,
http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
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Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakote Sprinkles should not be used to treat women with epilepsy who are pregnant or
who plan to become pregnant unless other treatments have failed to provide adequate
symptom control or are otherwise unacceptable. In such women, the benefits of treatment
with valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
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There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I.
104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
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social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in
this patient group, it should be used with extreme caution and as a sole agent. The benefits of
therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older
patient groups.
Younger children, especially those receiving enzyme inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults. The variability in free fraction limits the clinical
usefulness of monitoring total serum valproic acid concentration. Interpretation of valproic acid
concentrations in children should include consideration of factors that affect hepatic metabolism
and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were
shown to be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
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In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was
occasionally associated with the latter two events. It is not clear whether these events indicate
additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26) [see Clinical
Pharmacology (12.3)].
8.6 Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), Warnings and Precautions (5), and Clinical
Pharmacology (12.3)]. Liver disease impairs the capacity to eliminate valproate.
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however patients have recovered from valproate levels as high as 2,120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
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11 DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and
valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic
acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen
bis(2-propylpentanoate). Divalproex sodium has the following structure:
Divalproex sodium occurs as a white powder with a characteristic odor.
Depakote Sprinkle Capsules are for oral administration. Depakote Sprinkle Capsules contain
specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid in a hard
gelatin capsule.
Inactive Ingredients
125 mg Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Meets USP Dissolution Test 2.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms
by which valproate exerts its therapeutic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
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12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate may not
provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total
valproate, although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and DEPAKENE (valproic
acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to
8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and DEPAKENE formulations should cause no clinical problems in the management
of patients with epilepsy.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
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valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide)
[see Drug Interactions (7) for more detailed information on the pharmacokinetic interactions of
valproate with other drugs].
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Children
Pediatric patients (i.e., between 3 and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
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There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free
valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute
hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and
larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed
Warning, Contraindications (4), and Warnings and Precautions (5.1)].
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
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Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
14.1 Epilepsy
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy)
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 4. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment Number of Patients
Baseline Incidence
Experimental Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for valproate than placebo at
p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for valproate than for placebo. For example, 45% of patients treated with
valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of valproate to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to valproate. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 5. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of
Baseline Incidence Randomized Phase
Patients
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose valproate than for low dose valproate.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
valproate.
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakote Sprinkle Capsules (divalproex sodium coated particles in capsules), 125 mg, are white
opaque and blue, and are supplied in bottles of 100 (NDC 0074-6114-13) and Unit Dose
Packages of 100 (NDC 0074-6114-11).
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Recommended Storage
Store capsules below 77°F (25°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide.
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakote, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
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17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
17.8 Medication Residue in the Stool
Instruct patients to notify their healthcare provider if they notice a medication residue in the stool
[see Warnings and Precautions (5.18)].
17.9 Administration Guide
DEPAKOTE®
Sprinkle Capsules
DIVALPROEX SODIUM
COATED PARTICLES IN CAPSULES
DEPAKOTE® Sprinkle Capsules (divalproex sodium coated particles in capsules) may be
swallowed whole or the capsule contents may be sprinkled onto soft food such as applesauce or
pudding.
Serving Suggestions
Depakote ® Sprinkle Capsules (divalproex sodium coated particles in capsules) provide the
medicine that your healthcare provider has prescribed. The sprinkles are flavorless. Soft foods
such as applesauce or pudding are best to use for mixing and taking Depakote Sprinkles.
TO ADMINISTER WITH FOOD:
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us
ag
e
il
lu
st
ra
tion
Hold the capsule so that the end marked "THIS END UP" is straight up and the
arrow on the capsule is up. The capsule is extra large to help prevent spilling
the DEPAKOTE Sprinkles, but it still must be handled carefully.
To open the capsule, hold it carefully. As shown in the picture, gently twist the
capsule apart to separate the top from the bottom. It may be helpful to hold the
capsule over the food to which you will add the sprinkles. If you spill any of
the capsule contents, start over with a new capsule and a new portion of food.
Place all the sprinkles onto a small amount (about a teaspoonful) of soft food
such as applesauce or pudding.
Make sure that all of the sprinkle and food mixture is swallowed right away.
Do not chew the sprinkle and food mixture. Drinking water right after taking
the sprinkle and food mixture will help make sure all sprinkles are swallowed.
Throw away any unused sprinkle and food mixture; do not store any sprinkle
and food mixture for future use. Mix it each time, right before it is taken.
Make sure this medicine is taken exactly as your healthcare provider prescribed it. If you have
any questions, please contact your healthcare provider or pharmacist. Keep all of your healthcare
provider's appointments as scheduled. Make sure that Depakote Sprinkle Capsules and all other
medicines are kept out of the reach of children.
Note
You may see the specially coated particles in Depakote Sprinkle Capsules in stool. If you do, you
should inform your healthcare provider.
Ask your healthcare provider or pharmacist about possible side effects with Depakote Sprinkle
Capsules.
Store Depakote Sprinkle Capsules below 77°F (25°C).
AbbVie Inc.
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North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking a Depakote or Depakene and each time you
get a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote or Depakene?
Do not stop Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old. The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
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o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of childbearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
o severe stomach pain that you may also feel in your back
o nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
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o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status
epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder
• alone or with other medicines to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
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What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Administration Guide at the end of this Medication Guide for detailed instructions on
how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affects you. Depakote and Depakene can slow your thinking and motor skills.
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What are the possible side effects with Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene can cause serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering
and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips,
tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules between 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A915 Month Year
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid) capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence
seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
-------DOSAGE FORMS AND STRENGTHS-------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1) Suspected POLG-related disorder in
children under two years of age (4, 5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
• Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
Reference ID: 3520933
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
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death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
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Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
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regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
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dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
Reference ID: 3520933
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anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
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5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients
with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at
least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment
discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts
normalized with continued treatment. In this study, the probability of thrombocytopenia
appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or
≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should
therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
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mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
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higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
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Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
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Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
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Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
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Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea,
vomiting, and indigestion. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia
with some weight loss and increased appetite with weight gain have also been reported. The
administration of delayed-release divalproex sodium may result in reduction of gastrointestinal
side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most
often in patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema
multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been
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reported including a fatal case in a 6 month old infant taking valproate and several other
concomitant medications. An additional case of toxic epidermal necrosis resulting in death was
reported in a 35 year old patient with AIDS taking several concomitant medications and with a
history of multiple cutaneous drug reactions. Serious skin reactions have been reported with
concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and
behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis,
and frank hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and
appear to be dose-related. Occasionally, laboratory test results include increases in serum
bilirubin and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.5)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.9)], hyponatremia, and
inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a
cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain,
cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and
hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
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7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
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Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
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Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
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Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
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In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
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Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
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social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
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In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
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The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
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Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
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There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
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Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
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0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote Tablets
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A914 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Depakote safely and effectively. See full prescribing information for
Depakote.
Depakote (divalproex sodium) Tablets for Oral use
Initial U.S. Approval: 1983
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
• Hepatotoxicity, including fatalities, usually during the first 6 months
of treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 05/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Contraindications, Prophylaxis of Migraines in Pregnancy (4) 06/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
Warnings and Precautions, Medication Residue in the Stool (5.18) 02/2013
-------INDICATIONS AND USAGE-------
Depakote is an anti-epileptic drug indicated for:
• Treatment of manic episodes associated with bipolar disorder (1.1)
• Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence seizures; adjunctive therapy in patients with
multiple seizure types that include absence seizures (1.2)
• Prophylaxis of migraine headaches (1.3)
-------DOSAGE AND ADMINISTRATION-------
• Depakote is administered orally in divided doses. Depakote should be
swallowed whole and should not be crushed or chewed (2.1, 2.2).
• Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to
achieve therapeutic response or desired plasma level (2.1). The maximum
recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1
week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response;
if response is not satisfactory, check valproate plasma level; see full
prescribing information for conversion to monotherapy (2.2). The
maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by
5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The
maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Migraine: The recommended starting dose is 250 mg twice daily,
thereafter increasing to a maximum of 1000 mg/day as needed (2.3).
-------DOSAGE FORMS AND STRENGTHS-------
Tablets: 125 mg, 250 mg and 500 mg (3)
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
• Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy or bipolar disorder if other
medications are unacceptable; should not be administered to a woman of
childbearing potential unless essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakote should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakote,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status, and also with concomitant topiramate use; consider discontinuation
of valproate therapy (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakote (5.12)
• Somnolence in the elderly can occur. Depakote dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) reported in patients are
abdominal pain, accidental injury, alopecia, ambylopia/blurred vision,
amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation,
depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis,
emotional lability, fever, flu syndrome, headache, increased appetite,
infection, insomnia, nausea, nervousness, nystagmus, peripheral edema,
pharyngitis, rash, rhinitis, somnolence, thinking abnormal,
thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss
(6.1, 6.2, 6.3).
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
primidone, phenobarbital, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dose adjustment is indicated whenever enzyme-
inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations
are recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakote (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakote can cause congenital malformations including neural
tube defects and decreased IQ. (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1.3 Migraine
1 INDICATIONS AND USAGE
1.4 Important Limitations
1.1 Mania
2 DOSAGE AND ADMINISTRATION
1.2 Epilepsy
2.1 Mania
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2 Epilepsy
2.3 Migraine
2.4 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
5.18 Medication Residue in the Stool
6 ADVERSE REACTIONS
6.1 Mania
6.2 Epilepsy
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Mania
14.2 Epilepsy
14.3 Migraine
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
17.8 Medication Residue in the Stool
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate and its derivatives. These incidents usually have occurred during the first six
months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In
patients with epilepsy, a loss of seizure control may also occur. Patients should be
monitored closely for appearance of these symptoms. Serum liver tests should be
performed prior to therapy and at frequent intervals thereafter, especially during the first
six months [see Warnings and Precautions (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakote is used in this patient
group, it should be used with extreme caution and as a sole agent. The benefits of therapy
should be weighed against the risks. The incidence of fatal hepatotoxicity decreases
considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakote is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakote for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate is therefore contraindicated in pregnant women treated for prophylaxis of
migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant
women with epilepsy or bipolar disorder if other medications have failed to control their
symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
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is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Mania
Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic
episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and
persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure
of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor
judgment, aggressiveness, and possible hostility.
The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R
criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)].
The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks,
has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect
to use Depakote for extended periods should continually reevaluate the long-term usefulness of
the drug for the individual patient.
1.2 Epilepsy
Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with
complex partial seizures that occur either in isolation or in association with other types of
seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of
simple and complex absence seizures, and adjunctively in patients with multiple seizure types
that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
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1.3 Migraine
Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote
is useful in the acute treatment of migraine headaches.
1.4 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant.
2 DOSAGE AND ADMINISTRATION
Depakote tablets are intended for oral administration. Depakote tablets should be swallowed
whole and should not be crushed or chewed.
Patients should be informed to take Depakote every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
2.1 Mania
Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in
divided doses. The dose should be increased as rapidly as possible to achieve the lowest
therapeutic dose which produces the desired clinical effect or the desired range of plasma
concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a
clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum
concentrations were generally achieved within 14 days. The maximum recommended dosage is
60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer
term management of a patient who improves during Depakote treatment of an acute manic
episode. While it is generally agreed that pharmacological treatment beyond an acute response in
mania is desirable, both for maintenance of the initial response and for prevention of new manic
episodes, there are no data to support the benefits of Depakote in such longer-term treatment.
Although there are no efficacy data that specifically address longer-term antimanic treatment
with Depakote, the safety of Depakote in long-term use is supported by data from record reviews
involving approximately 360 patients treated with Depakote for greater than 3 months.
2.2 Epilepsy
Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive
therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years,
and in simple and complex absence seizures. As the Depakote dosage is titrated upward,
concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital,
carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
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Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at
10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal
clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or
phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may
interact with these or other concurrently administered AEDs as well as other drugs, periodic
plasma concentration determinations of concomitant AEDs are recommended during the early
course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
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The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentrations for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets
should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on
Depakote tablets, a dosing schedule of two or three times a day may be elected in selected
patients.
2.3 Migraine
Depakote is indicated for prophylaxis of migraine headaches in adults.
Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily.
Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no
evidence that higher doses led to greater efficacy.
2.4 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
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Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakote tablets (divalproex sodium delayed-release tablets) are supplied as:
125 mg salmon pink-colored tablets
250 mg peach-colored tablets
500 mg lavender-colored tablets
4 CONTRAINDICATIONS
• Depakote should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakote is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakote is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
• Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women
[see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
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those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakote is used in this patient group, it should be used with extreme caution and as a
sole agent. The benefits of therapy should be weighed against the risks. In progressively older
patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity
decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakote for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
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5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]),
carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of
migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to
become pregnant should not be treated with valproate unless other treatments have failed to
provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
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5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in
2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be
warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis
that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily
be discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders
Depakote is contraindicated in patients with known urea cycle disorders (UCD).
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakote, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
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The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo
Patients with
Events Per
1,000 Patients
Drug Patients
with Events
Per 1,000
Patients
Relative Risk: Incidence of
Events in Drug
Patients/Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients with Events
Per 1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakote or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126
patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of
platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with
return of platelet counts to normal. In the remaining patients, platelet counts normalized with
continued treatment. In this study, the probability of thrombocytopenia appeared to increase
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significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL
(males). The therapeutic benefit which may accompany the higher doses should therefore be
weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakote be monitored for platelet count and coagulation
parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of
hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
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topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.4)].
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5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
5.18 Medication Residue in the Stool
There have been rare reports of medication residue in the stool. Some patients have had anatomic
(including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI
transit times. In some reports, medication residues have occurred in the context of diarrhea. It is
recommended that plasma valproate levels be checked in patients who experience medication
residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated,
alternative treatment may be considered.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Mania
The incidence of treatment-emergent events has been ascertained based on combined data from
two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes
associated with bipolar disorder. The adverse reactions were usually mild or moderate in
intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of
premature termination due to intolerance were not statistically different between placebo,
Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy
due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively.
Table 2 summarizes those adverse reactions reported for patients in these trials where the
incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo
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incidence, or where the incidence in the Depakote-treated group was statistically significantly
greater than the placebo group. Vomiting was the only reaction that was reported by significantly
(p ≤ 0.05) more patients receiving Depakote compared to placebo.
Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During
Placebo-Controlled Trials of Acute Mania1
Adverse Reaction
Depakote
(n = 89)
Placebo
(n = 97)
Nausea
22%
15%
Somnolence
19%
12%
Dizziness
12%
4%
Vomiting
12%
3%
Accidental Injury
11%
5%
Asthenia
10%
7%
Abdominal pain
9%
8%
Dyspepsia
9%
8%
Rash
6%
3%
1. The following adverse reactions occurred at an equal or greater incidence for placebo than
for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.
The following additional adverse reactions were reported by greater than 1% but not more than
5% of the 89 Depakote-treated patients in controlled clinical trials:
Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.
Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension,
tachycardia, vasodilation.
Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal
abscess.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Edema, peripheral edema.
Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.
Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction,
confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia,
paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.
Respiratory System: Dyspnea, rhinitis.
Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis,
maculopapular rash, seborrhea.
Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.
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Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.
6.2 Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in the
placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to
determine whether the following adverse reactions can be ascribed to Depakote alone, or the
combination of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
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Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose valproate group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
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Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.3 Migraine
Based on two placebo-controlled clinical trials and their long term extension, valproate was
generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the
202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for
intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term
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extension study, the adverse reactions reported as the primary reason for discontinuation by ≥
1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight
gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression
(1%).
Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials
where the incidence rate in the Depakote-treated group was greater than 5% and was greater than
that for placebo patients.
Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During
Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking
Placebo1
Body System Reaction
Depakote
(N = 202)
Placebo
(N = 81)
Gastrointestinal System
Nausea
31%
10%
Dyspepsia
13%
9%
Diarrhea
12%
7%
Vomiting
11%
1%
Abdominal pain
9%
4%
Increased appetite
6%
4%
Nervous System
Asthenia
20%
9%
Somnolence
17%
5%
Dizziness
12%
6%
Tremor
9%
0%
Other
Weight gain
8%
2%
Back pain
8%
6%
Alopecia
7%
1%
1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at
an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis.
The following additional adverse reactions were reported by greater than 1% but not more than
5% of the 202 Depakote-treated patients in the controlled clinical trials:
Body as a Whole: Chest pain, chills, face edema, fever and malaise.
Cardiovascular System: Vasodilatation.
Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder
(unspecified), and stomatitis.
Hemic and Lymphatic System: Ecchymosis.
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Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.
Musculoskeletal System: Leg cramps and myalgia.
Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability,
insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.
Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.
Skin and Appendages: Pruritus and rash.
Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal
The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and
indigestion. These effects are usually transient and rarely require discontinuation of therapy.
Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some
weight loss and increased appetite with weight gain have also been reported. The administration
of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in
some patients.
CNS Effects
Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic
Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported
including a fatal case in a 6 month old infant taking valproate and several other concomitant
medications. An additional case of toxic epidermal necrosis resulting in death was reported in a
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35 year old patient with AIDS taking several concomitant medications and with a history of
multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant
administration of lamotrigine and valproate [see Drug Interactions (7.2)].
Psychiatric
Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal
Weakness.
Hematologic
Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected
in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank
hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic
Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to
be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and
abnormal changes in other liver function tests. These results may reflect potentially serious
hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine
Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic
Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].
Metabolic
Hyperammonemia [see Warnings and Precautions (5.9, 5.10)], hyponatremia, and inappropriate
ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary
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Enuresis and urinary tract infection.
Special Senses
Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other
Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia
[see Warnings and Precautions (5.11)].
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
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A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
in not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients
with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronosyltransferases.
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The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by
a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance
as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially
along with other anticonvulsants, should be monitored for alterations in serum concentrations of
both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
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Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase
in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The
fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
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Clozapine
In psychotic patients (n=11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder
[see Warnings and Precautions (5.2, 5.3)].
Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakote, physicians should
encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must
be done by the patients themselves. Information on the registry can be found at the website,
http://www.aedpregnancyregistry.org/.
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Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Valproate is contraindicated during pregnancy in women being treated for prophylaxis of
migraine headaches.
• Valproate should not be used to treat women with epilepsy or bipolar disorder who are
pregnant or who plan to become pregnant unless other treatments have failed to provide
adequate symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks. When treating a
pregnant woman or a woman of childbearing potential, carefully consider both the
potential risks and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
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• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I.
104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
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Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in
this patient group, it should be used with extreme caution and as a sole agent. The benefits of
therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older
patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
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on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were
shown to be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was
occasionally associated with the latter two events. It is not clear whether these events indicate
additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.4)].
There is insufficient information available to discern the safety and effectiveness of valproate for
the prophylaxis of migraines in patients over 65.
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however patients have recovered from valproate levels as high as 2,120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
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of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and
valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic
acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen
bis(2-propylpentanoate). Divalproex sodium has the following structure:
Divalproex sodium occurs as a white powder with a characteristic odor.
Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage
strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic
acid.
Inactive Ingredients
Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized
starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
In addition, individual tablets contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40.
250 mg tablets: FD&C Yellow No. 6 and iron oxide.
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms
by which valproate exerts its therapeutic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total
valproate, although some patients may be controlled with lower or higher plasma concentrations.
Mania
In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with
trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration
(2.1)].
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to
8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
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four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint. Whether
or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine
agent is unknown.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide)
[see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions
of valproate with other drugs].
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
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these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.4)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free
valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute
hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and
larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed
Warning, Contraindications (4) and Warnings and Precautions (5.1)].
Renal Disease
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A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
14.1 Mania
The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week,
placebo controlled, parallel group studies.
(1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar
disorder and who were hospitalized for acute mania. In addition, they had a history of failing to
respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a
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dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100
mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and
2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania
Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale
(BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline
in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows:
Table 6. Study 1
YMRS Total Score
Group
Baseline1
BL to Wk 32
Difference3
Placebo
28.8
+ 0.2
Depakote
28.5
- 9.5
9.7
BPRS-A Total Score
Group
Baseline1
BL to Wk 32
Difference3
Placebo
76.2
+ 1.8
Depakote
76.4
-17.0
18.8
GAS Score
Group
Baseline1
BL to Wk 32
Difference3
Placebo
31.8
0.0
Depakote
30.3
+ 18.1
18.1
1. Mean score at baseline
2. Change from baseline to Week 3 (LOCF)
3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and
placebo
Depakote was statistically significantly superior to placebo on all three measures of outcome.
(2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for
manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of
250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate
concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study
were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a
lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at
Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score
ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for
two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation
Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation
carry-forward) analysis were as follows:
Table 7. Study 2
MRS Total Score
Group
Baseline1
BL to Day 212
Difference3
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Placebo
38.9
- 4.4
Lithium
37.9
-10.5
6.1
Depakote
38.1
- 9.5
5.1
MSS Total Score
Group
Baseline1
BL to Day 212
Difference3
Placebo
18.9
- 2.5
Lithium
18.5
- 6.2
3.7
Depakote
18.9
- 6.0
3.5
BIS Total Score
Group
Baseline1
BL to Day 212
Difference3
Placebo
16.4
- 1.4
Lithium
16.0
- 3.8
2.4
Depakote
15.7
- 3.2
1.8
1. Mean score at baseline
2. Change from baseline to Day 21 (LOCF)
3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and
placebo and lithium and placebo
Depakote was statistically significantly superior to placebo on all three measures of outcome. An
exploratory analysis for age and gender effects on outcome did not suggest any differential
responsiveness on the basis of age or gender.
A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from
baseline in each treatment group, separated by study, is shown in Figure 1.
Figure 1
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
* p < 0.05
PBO = placebo, DVPX = Depakote
14.2 Epilepsy
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy)
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on
Treatment
Number
of Patients
Baseline
Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for valproate than placebo at p ≤
0.05 level.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for valproate than for placebo. For example, 45% of patients treated with
valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 2
The second study assessed the capacity of valproate to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to valproate. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of
Patients
Baseline
Incidence
Randomized
Phase Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose valproate than for low dose valproate.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
valproate.
Figure 3
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14.3 Migraine
The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials
established the effectiveness of Depakote in the prophylactic treatment of migraine headache.
Both studies employed essentially identical designs and recruited patients with a history of
migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2
migraine headaches a month during the 3 months prior to enrollment. Patients with cluster
headaches were excluded. Women of childbearing potential were excluded entirely from one
study, but were permitted in the other if they were deemed to be practicing an effective method
of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were
randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment
phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period.
Treatment outcome was assessed on the basis of 4-week migraine headache rates during the
treatment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were
randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period.
Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion.
Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain
the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over
500 mg were given in three divided doses (TID). The mean dose during the treatment phase was
1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31
to 133 mcg/mL.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo
group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly
different.
In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to
76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500
mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-
seven patients completed the 8-week maintenance period. Efficacy was to be determined by a
comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group
and placebo group.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days
for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate
levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000,
and 1,500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in
baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500,
1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4).
Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly
lower than in the placebo group.
Figure 4 Mean 4-week Migraine Rates
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1 Mean dose of Depakote was 1,087 mg/day.
2 Dose of Depakote was 500 or 1,000 mg/day.
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakote tablets (divalproex sodium delayed-release tablets) are supplied as:
125 mg salmon pink-colored tablets:
Bottles of 100………………………………………..(NDC 0074-6212-13)
Unit Dose Packages of 100.................………………(NDC 0074-6212-11)
250 mg peach-colored tablets:
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Bottles of 100……………………………………….(NDC 0074-6214-13)
Bottles of 500……………………………………….(NDC 0074-6214-53)
Unit Dose Packages of 100................………………(NDC 0074-6214-11)
500 mg lavender-colored tablets:
Bottles of 100……………………………………….(NDC 0074-6215-13)
Bottles of 500……………………………………….(NDC 0074-6215-53)
Unit Dose Packages of 100................……………...(NDC 0074-6215-11)
Recommended storage
Store tablets below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide.
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakote, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
17.8 Medication Residue in the Stool
Instruct patients to notify their healthcare provider if they notice a medication residue in the stool
[see Warnings and Precautions (5.18)].
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote or Depakene?
Do not stop Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of childbearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
o severe stomach pain that you may also feel in your back
o nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status
epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder
• alone or with other medicines to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Administration Guide at the end of this Medication Guide for detailed instructions on
how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affects you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects with Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote or Depakene can cause serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering
and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips,
tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Store Depakene Capsules between 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral Solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A929 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Depacon
safely and effectively. See full prescribing information for Depacon.
Depacon (valproate sodium) for intravenous injection
Initial U.S. Approval: 1996
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depacon is an anti-epileptic drug and is indicated as an intravenous alternative
in patients in whom oral administration of valproate products is temporarily
not feasible in the following conditions:
• Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence seizures; adjunctive therapy in patients with
multiple seizure types that include absence seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depacon is intended for intravenous use only.
• Epilepsy
o Complex Partial Seizures in Adults and Children 10 years of age or
older: Initial dose is 10 to 15 mg/kg/day, increasing at 1 week
intervals by 5 to10 mg/kg/day to achieve optimal clinical response.
Maximum recommended dose is 60 mg/kg/day (2.1).
o Simple and Complex Absence Seizures: Initial dose is 10 to 15
mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to
achieve optimal clinical response. Maximum recommended dose is
60 mg/kg/day (2.1).
-------DOSAGE FORMS AND STRENGTHS-------
Injection: 100 mg per mL in a 5 mL single dose vial (3)
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.11)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depacon should ordinarily be discontinued (5.5)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.7)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.8, 5.9)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.10)
• Multi-organ hypersensitivity reaction; discontinue Depacon (5.11)
• Somnolence in the elderly can occur. Depacon dosage should be increased
slowly and with regular monitoring for fluid and nutritional intake (5.13)
-------ADVERSE REACTIONS-------
Adverse reactions occurring in at least 5% of patients treated with Depakote in
Monotherapy or Adjunctive Complex Partial Seizures Trials:
• Abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia,
asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia,
dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu
syndrome, headache, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss (6.1)
Additional Adverse Reactions not included above that occurred in > 0.5% of
patients treated with Depacon:
• Chest pain, euphoria, hypesthesia, injection site inflammation, injection
site pain, injection site reaction, pain, sweating, taste perversion,
vasodilation (6)
Additional adverse reactions not included above that occurred in other clinical
trials with Depakote:
• Accidental injury, back pain, increased appetite, rash (6)
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depacon (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depacon can cause congenital malformations including neural
tube defects and decreased IQ. (5.2, 5.3 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose, increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.13, 8.5)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
3 DOSAGE FORMS AND STRENGTHS
1 INDICATIONS AND USAGE
4 CONTRAINDICATIONS
1.1 Epilepsy
5 WARNINGS AND PRECAUTIONS
1.2 Important Limitations
5.1 Hepatotoxicity
2 DOSAGE AND ADMINISTRATION
5.2 Birth Defects
2.1 Epilepsy
5.3 Decreased IQ Following in utero Exposure
2.2 General Dosing Advice
5.4 Use in Women of Childbearing Potential
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5.5 Pancreatitis
5.6 Urea Cycle Disorders
5.7 Thrombocytopenia
5.8 Hyperammonemia
5.9 Hyperammonemia and Encephalopathy associated with Concomitant
Topiramate Use
5.10 Hypothermia
5.11 Multi-Organ Hypersensitivity Reactions
5.12 Interaction with Carbapenem Antibiotics
5.13 Somnolence in the Elderly
5.14 Post-traumatic Seizures
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Hyperammonemia
17.5 CNS Depression
17.6 Multi-Organ Hypersensitivity Reactions
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate and its derivatives. These incidents usually have occurred during the first six
months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In
patients with epilepsy, a loss of seizure control may also occur. Patients should be
monitored closely for appearance of these symptoms. Serum liver tests should be
performed prior to therapy and at frequent intervals thereafter, especially during the first
six months [see Warnings and Precautions (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depacon is used in this patient
group, it should be used with extreme caution and as a sole agent. The benefits of therapy
should be weighed against the risks. The incidence of fatal hepatotoxicity decreases
considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depacon is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depacon should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depacon for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
Reference ID: 3520933
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death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4) and Patient Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depacon is indicated as an intravenous alternative in patients for whom oral administration of
valproate products is temporarily not feasible in the following conditions:
Depacon is indicated as monotherapy and adjunctive therapy in the treatment of patients with
complex partial seizures that occur either in isolation or in association with other types of
seizures. Depacon is also indicated for use as sole and adjunctive therapy in the treatment of
patients with simple and complex absence seizures, and adjunctively in patients with multiple
seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precautions (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depacon is for intravenous use only.
Use of Depacon for periods of more than 14 days has not been studied. Patients should be
switched to oral valproate products as soon as it is clinically feasible.
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Depacon should be administered as a 60 minute infusion (but not more than 20 mg/min) with the
same frequency as the oral products, although plasma concentration monitoring and dosage
adjustments may be necessary.
In one clinical safety study, approximately 90 patients with epilepsy and with no measurable
plasma levels of valproate were given single infusions of Depacon (up to 15 mg/kg and mean
dose of 1184 mg) over 5-10 minutes (1.5-3.0 mg/kg/min). Patients generally tolerated the more
rapid infusions well [see Adverse Reactions (6.1)]. This study was not designed to assess the
effectiveness of these regimens. For pharmacokinetics with rapid infusions, see Clinical
Pharmacology (12.3).
Initial Exposure to Valproate
The following dosage recommendations were obtained from studies utilizing oral divalproex
sodium products.
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depacon has not been systematically studied as initial therapy. Patients should initiate therapy at
10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal
clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depacon therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
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Depacon may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or
phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact
with these or other concurrently administered AEDs as well as other drugs, periodic plasma
concentration determinations of concomitant AEDs are recommended during the early course of
therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depacon dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
Replacement Therapy
When switching from oral valproate products, the total daily dose of Depacon should be
equivalent to the total daily dose of the oral valproate product [see Clinical Pharmacology (12)],
and should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same
frequency as the oral products, although plasma concentration monitoring and dosage
adjustments may be necessary. Patients receiving doses near the maximum recommended daily
dose of 60 mg/kg/day, particularly those not receiving enzyme-inducing drugs, should be
monitored more closely. If the total daily dose exceeds 250 mg, it should be given in a divided
regimen. There is no experience with more rapid infusions in patients receiving Depacon as
replacement therapy. However, the equivalence shown between Depacon and oral valproate
products (Depakote) at steady state was only evaluated in an every 6 hour regimen. Whether,
when Depacon is given less frequently (i.e., twice or three times a day), trough levels fall below
those that result from an oral dosage form given via the same regimen, is unknown. For this
reason, when Depacon is given twice or three times a day, close monitoring of trough plasma
levels may be needed.
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2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
Administration
Rapid infusion of Depacon has been associated with an increase in adverse reactions. There is
limited experience with infusion times of less than 60 minutes or rates of infusion > 20 mg/min
in patients with epilepsy [see Adverse Reactions (6)].
Depacon should be administered intravenously as a 60 minute infusion, as noted above. It should
be diluted with at least 50 mL of a compatible diluent. Any unused portion of the vial contents
should be discarded.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Compatibility and Stability
Depacon was found to be physically compatible and chemically stable in the following
parenteral solutions for at least 24 hours when stored in glass or polyvinyl chloride (PVC) bags
at controlled room temperature 15-30°C (59-86°F).
• dextrose (5%) injection, USP
• sodium chloride (0.9%) injection, USP
• lactated ringer's injection, USP
3 DOSAGE FORMS AND STRENGTHS
Depacon (valproate sodium injection), equivalent to 100 mg of valproic acid per mL, is a clear,
colorless solution in 5 mL single-dose vials, available in trays of 10 vials.
Recommended storage: Store vials at controlled room temperature 15-30°C (59-86°F). No
preservatives have been added. Unused portion of container should be discarded.
Reference ID: 3520933
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4 CONTRAINDICATIONS
• Depacon should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depacon is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depacon is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.11)].
• Depacon is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months of valproate therapy. However, physicians should not rely totally on serum biochemistry
since these tests may not be abnormal in all instances, but should also consider the results of
careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depacon is used in this patient group, it should be used with extreme caution and as a sole
agent. The benefits of therapy should be weighed against the risks. Use of Depacon has not been
studied in children below the age of 2 years. In progressively older patient groups experience in
epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depacon is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Reference ID: 3520933
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Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depacon should only be used after other anticonvulsants have failed. This
older group of patients should be closely monitored during treatment with Depacon for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]),
carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
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Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
Reference ID: 3520933
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5.6 Urea Cycle Disorders
Valproate sodium is contraindicated in patients with known urea cycle disorders (UCD).
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.9)].
5.7 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126
patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of
platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with
return of platelet counts to normal. In the remaining patients, platelet counts normalized with
continued treatment. In this study, the probability of thrombocytopenia appeared to increase
significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL
(males). The therapeutic benefit which may accompany the higher doses should therefore be
weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depacon be monitored for platelet count and coagulation
parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of
hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
5.8 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.10)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.9)].
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Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.9 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.10)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.8)].
5.10 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.11 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
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experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.12 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.13 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.14 Post-traumatic Seizures
A study was conducted to evaluate the effect of IV valproate in the prevention of post-traumatic
seizures in patients with acute head injuries. Patients were randomly assigned to receive either
IV valproate given for one week (followed by oral valproate products for either one or six
months per random treatment assignment) or IV phenytoin given for one week (followed by
placebo). In this study, the incidence of death was found to be higher in the two groups assigned
to valproate treatment compared to the rate in those assigned to the IV phenytoin treatment group
(13% vs. 8.5%, respectively). Many of these patients were critically ill with multiple and/or
severe injuries, and evaluation of the causes of death did not suggest any specific drug-related
causation. Further, in the absence of a concurrent placebo control during the initial week of
intravenous therapy, it is impossible to determine if the mortality rate in the patients treated with
valproate was greater or less than that expected in a similar group not treated with valproate, or
whether the rate seen in the IV phenytoin treated patients was lower than would be expected.
Nonetheless, until further information is available, it seems prudent not to use Depacon in
patients with acute head trauma for the prophylaxis of post-traumatic seizures.
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
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5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
The adverse reactions that can result from Depacon use include all of those associated with oral
forms of valproate. The following describes experience specifically with Depacon. Depacon has
been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and
352 patients with epilepsy, given at doses of 125 to 6,000 mg (total daily dose). A total of 2% of
patients discontinued treatment with Depacon due to adverse reactions. The most common
adverse reactions leading to discontinuation were 2 cases each of nausea/vomiting and elevated
amylase. Other adverse reactions leading to discontinuation were hallucinations, pneumonia,
headache, injection site reaction, and abnormal gait. Dizziness and injection site pain were
observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200
mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate.
The maximum rate of infusion studied was 200 mg/min.
Adverse reactions reported by at least 0.5% of all subjects/patients in clinical trials of Depacon
are summarized in Table 1.
Table 1. Adverse Reactions Reported During Studies of Depacon
Body System/Reaction
N = 463
Body as a Whole
Chest Pain
1.7%
Headache
4.3%
Injection Site Inflammation
0.6%
Injection Site Pain
2.6%
Injection Site Reaction
2.4%
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Pain (unspecified)
1.3%
Cardiovascular
Vasodilation
0.9%
Dermatologic
Sweating
0.9%
Digestive System
Abdominal Pain
1.1%
Diarrhea
0.9%
Nausea
3.2%
Vomiting
1.3%
Nervous System
Dizziness
5.2%
Euphoria
0.9%
Hypesthesia
0.6%
Nervousness
0.9%
Paresthesia
0.9%
Somnolence
1.7%
Tremor
0.6%
Respiratory
Pharyngitis
0.6%
Special Senses
Taste Perversion
1.9%
In a separate clinical safety trial, 112 patients with epilepsy were given infusions of Depacon (up
to 15 mg/kg) over 5 to 10 minutes (1.5-3.0 mg/kg/min). The common adverse reactions (> 2%)
were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%),
and headache (2.7%). While the incidence of these adverse reactions was generally higher than
in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence
(1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache
(4.3%), a direct comparison between the incidence of adverse reactions in the 2 cohorts cannot
be made because of differences in patient populations and study designs.
Ammonia levels have not been systematically studied after IV valproate, so that an estimate of
the incidence of hyperammonemia after IV Depacon cannot be provided. Hyperammonemia with
encephalopathy has been reported in 2 patients after infusions of Depacon.
6.1 Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote (divalproex sodium) was generally well tolerated with most adverse reactions
rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in
the Depakote-treated patients (6%), compared to 1% of placebo-treated patients.
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Table 2 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in the
placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to
determine whether the following adverse reactions can be ascribed to Depakote alone, or the
combination of Depakote and other antiepilepsy drugs.
Table 2. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
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Alopecia
6
1
Weight Loss
6
0
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose valproate group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
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Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depacon has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
(Divalproex Sodium) tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
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Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital: Dysuria.
6.3 Migraine
Although Depacon has not been evaluated for safety and efficacy in the prophylactic treatment of
migraine headaches, the following adverse reactions not listed above were reported by 1% or
more of patients from two placebo-controlled clinical trials of Depakote (Divalproex Sodium)
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea,
vomiting, and indigestion. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia
with some weight loss and increased appetite with weight gain have also been reported. The
administration of delayed-release divalproex sodium may result in reduction of gastrointestinal
side effects in some patients using oral therapy.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most
often in patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes," dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema
multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been
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reported including a fatal case in a 6 month old infant taking valproate and several other
concomitant medications. An additional case of toxic epidermal necrosis resulting in death was
reported in a 35 year old patient with AIDS taking several concomitant medications and with a
history of multiple cutaneous drug reactions. Serious skin reactions have been reported with
concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and
behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis,
and frank hemorrhage [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and
appear to be dose-related. Occasionally, laboratory test results include increases in serum
bilirubin and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic: Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and
inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a
cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain,
cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and
hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
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7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem this is
not a complete list) and may result in loss of seizure control. The mechanism of this interaction is
not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.12)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyl transferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
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Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
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Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
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Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 µg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.8, 5.9)]. Concomitant administration of topiramate with valproate has also
been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.8, 5.10)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depacon, physicians should
encourage pregnant patients taking Depacon to enroll in the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must
be done by the patients themselves. Information on the registry can be found at the website,
http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
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In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Valproate should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.7)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
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Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% - 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 - 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% C.I. 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% C.I. 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I.
104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
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social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience with oral valproate has indicated that pediatric patients under the age of two years are
at a considerably increased risk of developing fatal hepatotoxicity, especially those with the
aforementioned conditions [see Boxed Warning]. The safety of Depacon has not been studied in
individuals below the age of 2 years. If a decision is made to use Depacon in this age group, it
should be used with extreme caution and as a sole agent. The benefits of therapy should be
weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the
incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproate concentrations.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
No unique safety concerns were identified in the 35 patients age 2 to 17 years who received
Depacon in clinical trials.
One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in
the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of
Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse
Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was
occasionally associated with the latter two events. It is not clear whether these events indicate
additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
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A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
No unique safety concerns were identified in the 21 patients > 65 years of age receiving Depacon
in clinical trials.
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however patients have recovered from valproate serum concentrations as
high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. General
supportive measures should be applied with particular attention to the maintenance of adequate
urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepilepsy effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depacon (valproate sodium) is the sodium salt of valproic acid designated as sodium 2
propylpentanoate. Valproate sodium has the following structure:
Valproate sodium has a molecular weight of 166.2. It occurs as an essentially white and odorless,
crystalline, deliquescent powder.
Depacon solution is available in 5 mL single-dose vials for intravenous injection. Each mL
contains valproate sodium equivalent to 100 mg valproic acid, edetate disodium 0.40 mg, and
water for injection to volume. The pH is adjusted to 7.6 with sodium hydroxide and/or
hydrochloric acid. The solution is clear and colorless.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Depacon exists as the valproate ion in the blood. The mechanisms by which valproate exerts its
therapeutic effects have not been established. It has been suggested that its activity in epilepsy is
related to increased brain concentrations of gamma-aminobutyric acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total
valproate, although some patients may be controlled with lower or higher plasma concentrations.
Equivalent doses of Depacon and Depakote (divalproex sodium) yield equivalent plasma levels
of the valproate ion [see Clinical Pharmacology (12.3)].
12.3 Pharmacokinetics
Bioavailability
Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result
in equivalent Cmax, Cmin, and total systemic exposure to the valproate ion when the IV valproate
is administered as a 60 minute infusion. However, the rate of valproate ion absorption may vary
with the formulation used. These differences should be of minor clinical importance under the
steady state conditions achieved in chronic use in the treatment of epilepsy.
Administration of Depakote (divalproex sodium) tablets and IV valproate (given as a one hour
infusion), 250 mg every 6 hours for 4 days to 18 healthy male volunteers resulted in equivalent
AUC, Cmax, Cmin at steady state, as well as after the first dose. The Tmax after IV Depacon occurs
at the end of the one hour infusion, while the Tmax after oral dosing with Depakote occurs at
approximately 4 hours. Because the kinetics of unbound valproate are linear, bioequivalence
between Depacon and Depakote up to the maximum recommended dose of 60 mg/kg/day can be
assumed. The AUC and Cmax resulting from administration of IV valproate 500 mg as a single
one hour infusion and a single 500 mg dose of Depakene syrup to 17 healthy male volunteers
were also equivalent.
Patients maintained on valproic acid doses of 750 mg to 4250 mg daily (given in divided doses
every 6 hours) as oral Depakote (divalproex sodium) alone (n = 24) or with another stabilized
antiepileptic drug [carbamazepine (n = 15), phenytoin (n = 11), or phenobarbital (n = 1)],
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showed comparable plasma levels for valproic acid when switching from oral Depakote to IV
valproate (1-hour infusion).
Eleven healthy volunteers were given single infusions of 1000 mg IV valproate over 5, 10, 30,
and 60 minutes in a 4-period crossover study. Total valproate concentrations were measured;
unbound concentrations were not measured. After the 5 minute infusions (mean rate of 2.8
mg/kg/min), mean Cmax was 145 ± 32 mcg/mL, while after the 60 minute infusions, mean Cmax
was 115 ± 8 mcg/mL. Ninety to 120 minutes after infusion initiation, total valproate
concentrations were similar for all 4 rates of infusion. Because protein binding is nonlinear at
higher total valproate concentrations, the corresponding increase in unbound Cmax at faster
infusion rates will be greater.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide)
(see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of
valproate with other drugs).
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean terminal half-life for valproate monotherapy after an
intravenous infusion of 1,000 mg was 16 ± 3.0 hours.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
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Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free
valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute
hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and
larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed
Warning, Contraindications (4), and Warnings and Precautions (5.1)].
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
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necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD dose on a mg/m2 basis) for
60 days. The effect of valproate on testicular development and on sperm production and fertility
in humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted with oral divalproex sodium
products.
14.1 Epilepsy
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
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original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 4. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05
level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for valproate than for placebo. For example, 45% of patients treated with
valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The second study assessed the capacity of valproate to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to valproate. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 5. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose valproate than for low dose valproate.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
valproate.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depacon (valproate sodium injection), equivalent to 100 mg of valproic acid per mL, is a clear,
colorless solution in 5 mL single-dose vials, available in trays of 10 vials (NDC 0074-1564-10).
Recommended storage: Store vials at controlled room temperature 15-30°C (59-86°F). No
preservatives have been added. Unused portion of container should be discarded.
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
17.4 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.8, 5.9)].
17.5 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.6 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.11)].
Manufactured at
Hospira, Inc.
McPherson, KS 67460 USA
Manufactured by
Hospira, Inc.
Lake Forest, IL 60045 USA
For
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
AbbVie Inc.
North Chicago, IL 60064, U.S.A.
EN-3483 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
2025-02-12T13:44:34.971393
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018081s060,018082s043,018723s052,019680s039,020593s030,021168s028lbl.pdf', 'application_number': 18081, 'submission_type': 'SUPPL ', 'submission_number': 60}
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11,153
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid), capsules, USP, for oral use
DEPAKENE (valproic acid) oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
RECENT MAJOR CHANGES
Warnings and Precautions, Birth Defects (5.2)
1/2015
Warnings and Precautions, Bleeding and Other Hematopeietic
Disorders (5.8)
1/2015
Warnings and Precautions, Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reaction
1/2015
(5.12)
INDICATIONS AND USAGE
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence seizures
(1)
DOSAGE AND ADMINISTRATION
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
DOSAGE FORMS AND STRENGTHS
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
CONTRAINDICATIONS
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial DNA
polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
WARNINGS AND PRECAUTIONS
• Hepatotoxicity; evaluate high risk populations and monitor serum liver tests
(5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Bleeding and other hematopoietic disorders; monitor platelet counts and
coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy with
or without associated hyperammonemia. This adverse reaction can also
occur in patients using concomitant topiramate (5.11)
• Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan hypersensitivity reaction; discontinue Depakene
(5.12)
• Somnolence in the elderly can occur. Depakene dosage should be increased
slowly and with regular monitoring for fluid and nutritional intake (5.14)
ADVERSE REACTIONS
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance, while
enzyme inhibitors (e.g., felbamate) can decrease valproate clearance.
Therefore increased monitoring of valproate and concomitant drug
concentrations and dosage adjustment are indicated whenever enzyme-
inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine
may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
USE IN SPECIFIC POPULATIONS
• Pregnancy: Depakene can cause congenital malformations including neural
tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid
and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 3/2015
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Bleeding and Other Hematopoietic Disorders
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
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5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The
rate of congenital malformations among babies born to mothers using valproate is about four
times higher than the rate among babies born to epileptic mothers using other anti-seizure
monotherapies. Evidence suggests that folic acid supplementation prior to conception and during
the first trimester of pregnancy decreases the risk for congenital neural tube defects in the
general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Bleeding and Other Hematopoietic Disorders
Valproate is associated with dose-related thrombocytopenia. In a clinical trial of Depakote
(divalproex sodium) as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving
approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L.
Approximately half of these patients had treatment discontinued, with return of platelet counts to
normal. In the remaining patients, platelet counts normalized with continued treatment. In this
study, the probability of thrombocytopenia appeared to increase significantly at total valproate
concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit
which may accompany the higher doses should therefore be weighed against the possibility of a
greater incidence of adverse effects. Valproate use has also been associated with decreases in
other cell lines and myelodysplasia.
Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired
von Willebrand’s disease), measurements of complete blood counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended that patients
receiving Depakene (valproic acid) be monitored for blood counts and coagulation parameters
prior to planned surgery and during pregnancy [see Use in Specific Populations (8.1)]. Evidence
of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of
the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
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not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity Reactions
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy, in association with other organ system involvement, such as hepatitis,
nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute
viral infection. Eosinophilia is often present. Because this disorder is variable in its expression,
other organ systems not noted here may be involved. It is important to note that early
manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even
though rash is not evident. If such signs or symptoms are present, the patient should be evaluated
immediately. Valproate should be discontinued and not be resumed if an alternative etiology for
the signs or symptoms cannot be established.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
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higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
• Hepatic failure [see Warnings and Precautions (5.1)]
• Birth defects [see Warnings and Precautions (5.2)]
• Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
• Pancreatitis [see Warnings and Precautions (5.5)]
• Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
• Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
• Hypothermia [see Warnings and Precautions (5.11)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
hypersensitivity reactions [see Warnings and Precautions (5.12)]
• Somnolence in the elderly [see Warnings and Precautions (5.14)]
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Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
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Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
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Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
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6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience
The following adverse reactions have been identified during post approval use of Depakote.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Dermatologic: Hair texture changes, hair color changes, photosensitivity, erythema multiforme,
toxic epidermal necrolysis, and Stevens-Johnson syndrome.
Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility,
disturbance in attention, learning disorder, and behavioral deterioration.
Neurologic: There have been several reports of acute or subacute cognitive decline and
behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated
with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy
reversed partially or fully after valproate discontinuation.
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Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and
weakness.
Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic
with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia,
agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated
testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary
disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate
ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss.
Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and
cutaneous vasculitis.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For
example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance
of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher
concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-
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valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
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7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
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lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
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Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
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To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations, hypospadias, limb malformations). The risk of major structural abnormalities is
greatest during the first trimester; however, other serious developmental effects can occur with
valproate use throughout pregnancy. The rate of congenital malformations among babies born to
epileptic mothers who used valproate during pregnancy has been shown to be about four times
higher than the rate among babies born to epileptic mothers who used other anti-seizure
monotherapies [see Warnings and Precautions (5.3)].
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
An observational study has suggested that exposure to valproate products during pregnancy may
increase the risk of autism spectrum disorders. In this study, children born to mothers who had
used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]:
1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not
exposed to valproate products during pregnancy. The absolute risks for autism spectrum
disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI:
1.5%-1.6%) in children not exposed to valproate products. Because the study was observational
in nature, conclusions regarding a causal association between in utero valproate exposure and an
increased risk of autism spectrum disorder cannot be considered definitive.
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
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• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Pregnant women taking valproate may develop clotting abnormalities including
thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which
may result in hemorrhagic complications in the neonate including death [see Warnings and
Precautions (5.8)]. If valproate is used in pregnancy, the clotting parameters should be
monitored carefully in the mother. If abnormal in the mother, then these parameters should
also be monitored in the neonate.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
• Hypoglycemia has been reported in neonates whose mothers have taken valproate during
pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the
offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during
pregnancy. These data show up to a five-fold increased risk for any major malformation
following valproate exposure in utero compared to the risk following exposure in utero to other
antiepileptic drugs taken in monotherapy. The major congenital malformations included cases of
neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts,
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craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and
malformations of varying severity involving other body systems.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
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patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
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these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, deep coma and
hypernatremia. Fatalities have been reported; however, patients have recovered from valproate
levels as high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
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Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
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Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Reference ID: 3715513
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Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
Reference ID: 3715513
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phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
Reference ID: 3715513
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15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
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Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
Multiorgan Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium delayed release capsules)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
Reference ID: 3715513
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◦ nausea or vomiting that does not go away
◦ loss of appetite
◦ pain on the right side of your stomach (abdomen)
◦ dark urine
◦ swelling of your face
◦ yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
◦ If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects that affect the brain and spinal cord and are called
spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies
born to mothers who use this medicine during pregnancy. These defects can begin in the
first month, even before you know you are pregnant. Other birth defects that affect the
structures of the heart, head, arms, legs, and the opening where the urine comes out
(urethra) on the bottom of the penis can also happen.
◦ Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
◦ Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
◦ If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
◦ There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
◦ Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
◦ All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
◦ Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
◦ Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
Reference ID: 3715513
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◦ thoughts about suicide or dying
◦ attempts to commit suicide
◦ new or worse depression
◦ new or worse anxiety
◦ feeling agitated or restless
◦ panic attacks
◦ trouble sleeping (insomnia)
◦ new or worse irritability
◦ acting aggressive, being angry, or violent
◦ acting on dangerous impulses
◦ an extreme increase in activity and talking (mania)
◦ other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
◦ Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
◦ Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
◦ complex partial seizures in adults and children 10 years of age and older
◦ simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
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• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you cannot swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
Reference ID: 3715513
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your
joints due to bleeding or bleeding from your mouth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
Reference ID: 3715513
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For current labeling information, please visit https://www.fda.gov/drugsatfda
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
Reference ID: 3715513
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: March 2015
Reference ID: 3715513
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid), capsules, USP, for oral use
DEPAKENE (valproic acid) oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
RECENT MAJOR CHANGES
Dosage and Administration, Dosing in Patients Taking Rufinamide
(2.3)
2/2016
INDICATIONS AND USAGE
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence seizures
(1)
DOSAGE AND ADMINISTRATION
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
DOSAGE FORMS AND STRENGTHS
Capsules: 250 mg valproic acid (3)
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt (3)
CONTRAINDICATIONS
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial DNA
polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
WARNINGS AND PRECAUTIONS
• Hepatotoxicity; evaluate high risk populations and monitor serum liver tests
(5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Bleeding and other hematopoietic disorders; monitor platelet counts and
coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status, and also with concomitant topiramate use; consider discontinuation
of valproate therapy (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy with
or without associated hyperammonemia. This adverse reaction can also
occur in patients using concomitant topiramate (5.11)
• Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan hypersensitivity reaction; discontinue Depakene
(5.12)
• Somnolence in the elderly can occur. Depakene dosage should be increased
slowly and with regular monitoring for fluid and nutritional intake (5.14)
ADVERSE REACTIONS
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance, while
enzyme inhibitors (e.g., felbamate) can decrease valproate clearance.
Therefore increased monitoring of valproate and concomitant drug
concentrations and dosage adjustment are indicated whenever enzyme-
inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Patients stabilized on rufinamide should begin valproate therapy at a low
dose, and titrate to clinically effective dose (7.2)
• Dosage adjustment of amitriptyline/nortriptyline, warfarin, and zidovudine
may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
USE IN SPECIFIC POPULATIONS
• Pregnancy: Depakene can cause congenital malformations including neural
tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid
and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 2/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
4 CONTRAINDICATIONS
WARNING: LIFE THREATENING ADVERSE REACTIONS
5 WARNINGS AND PRECAUTIONS
1 INDICATIONS AND USAGE
5.1 Hepatotoxicity
1.1 Epilepsy
5.2 Birth Defects
1.2 Important Limitations
5.3 Decreased IQ Following in utero Exposure
2 DOSAGE AND ADMINISTRATION
5.4 Use in Women of Childbearing Potential
2.1 Epilepsy
5.5 Pancreatitis
2.2 General Dosing Advice
5.6 Urea Cycle Disorders (UCD)
2.3 Dosing in Patients Taking Rufinamide
5.7 Suicidal Behavior and Ideation
3 DOSAGE FORMS AND STRENGTHS
5.8 Bleeding and Other Hematopoietic Disorders
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5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
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death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
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Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
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regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
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dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
2.3 Dosing in Patients Taking Rufinamide
Patients stabilized on rufinamide before being prescribed valproate should begin valproate
therapy at a low dose, and titrate to a clinically effective dose [see Drug Interactions (7.2)].
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
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5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
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In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The
rate of congenital malformations among babies born to mothers using valproate is about four
times higher than the rate among babies born to epileptic mothers using other anti-seizure
monotherapies. Evidence suggests that folic acid supplementation prior to conception and during
the first trimester of pregnancy decreases the risk for congenital neural tube defects in the
general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
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5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
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hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
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Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Bleeding and Other Hematopoietic Disorders
Valproate is associated with dose-related thrombocytopenia. In a clinical trial of Depakote
(divalproex sodium) as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving
approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L.
Approximately half of these patients had treatment discontinued, with return of platelet counts to
normal. In the remaining patients, platelet counts normalized with continued treatment. In this
study, the probability of thrombocytopenia appeared to increase significantly at total valproate
concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit
which may accompany the higher doses should therefore be weighed against the possibility of a
greater incidence of adverse effects. Valproate use has also been associated with decreases in
other cell lines and myelodysplasia.
Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired
von Willebrand’s disease), measurements of complete blood counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended that patients
receiving Depakene (valproic acid) be monitored for blood counts and coagulation parameters
prior to planned surgery and during pregnancy [see Use in Specific Populations (8.1)]. Evidence
of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of
the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
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Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. Patients with inborn errors of metabolism or reduced
hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity Reactions
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy, in association with other organ system involvement, such as hepatitis,
nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute
viral infection. Eosinophilia is often present. Because this disorder is variable in its expression,
other organ systems not noted here may be involved. It is important to note that early
manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even
though rash is not evident. If such signs or symptoms are present, the patient should be evaluated
immediately. Valproate should be discontinued and not be resumed if an alternative etiology for
the signs or symptoms cannot be established.
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5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
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• Hepatic failure [see Warnings and Precautions (5.1)]
• Birth defects [see Warnings and Precautions (5.2)]
• Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
• Pancreatitis [see Warnings and Precautions (5.5)]
• Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
• Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
• Hypothermia [see Warnings and Precautions (5.11)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
hypersensitivity reactions [see Warnings and Precautions (5.12)]
• Somnolence in the elderly [see Warnings and Precautions (5.14)]
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
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Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
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Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
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Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience
The following adverse reactions have been identified during post approval use of Depakote.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
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Dermatologic: Hair texture changes, hair color changes, photosensitivity, erythema multiforme,
toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.
Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility,
disturbance in attention, learning disorder, and behavioral deterioration.
Neurologic: There have been several reports of acute or subacute cognitive decline and
behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated
with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy
reversed partially or fully after valproate discontinuation.
Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and
weakness.
Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic
with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia,
agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated
testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary
disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate
ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Metabolism and nutrition: Weight gain.
Reproductive: Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility,
male infertility, and abnormal spermatozoa morphology.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss.
Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and
cutaneous vasculitis.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For
example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance
of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher
concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
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Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Cholestyramine
Cholestyramine, when concurrently administered with valproic acid, led to, on average, a 14%
decrease in plasma levels of valproic acid in a study conducted in 6 healthy subjects
administered Depakene (valproic acid) and cholestyramine. Delaying the administration of
cholestyramine relative to valproic acid administration by 3 hours may lessen the interaction.
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
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Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
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The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
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presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Rufinamide
Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by
valproate. Rufinamide concentrations were increased by <16% to 70%, dependent on
concentration of valproate (with the larger increases being seen in pediatric patients at high doses
or concentrations of valproate). Patients stabilized on rufinamide before being prescribed
valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose
[see Dosage and Administration (2.3)]. Similarly, patients on valproate should begin at a
rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults).
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
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Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations, hypospadias, limb malformations). The risk of major structural abnormalities is
greatest during the first trimester; however, other serious developmental effects can occur with
valproate use throughout pregnancy. The rate of congenital malformations among babies born to
epileptic mothers who used valproate during pregnancy has been shown to be about four times
higher than the rate among babies born to epileptic mothers who used other anti-seizure
monotherapies [see Warnings and Precautions (5.3)].
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Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
An observational study has suggested that exposure to valproate products during pregnancy may
increase the risk of autism spectrum disorders. In this study, children born to mothers who had
used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]:
1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not
exposed to valproate products during pregnancy. The absolute risks for autism spectrum
disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI:
1.5%-1.6%) in children not exposed to valproate products. Because the study was observational
in nature, conclusions regarding a causal association between in utero valproate exposure and an
increased risk of autism spectrum disorder cannot be considered definitive.
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
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offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Pregnant women taking valproate may develop clotting abnormalities including
thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which
may result in hemorrhagic complications in the neonate including death [see Warnings and
Precautions (5.8)]. If valproate is used in pregnancy, the clotting parameters should be
monitored carefully in the mother. If abnormal in the mother, then these parameters should
also be monitored in the neonate.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
• Hypoglycemia has been reported in neonates whose mothers have taken valproate during
pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the
offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during
pregnancy. These data show up to a five-fold increased risk for any major malformation
following valproate exposure in utero compared to the risk following exposure in utero to other
antiepileptic drugs taken in monotherapy. The major congenital malformations included cases of
neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts,
craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and
malformations of varying severity involving other body systems.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
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There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
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The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, deep coma, and
hypernatremia. Fatalities have been reported; however, patients have recovered from valproate
levels as high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
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11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure: structural formula
Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
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Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
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Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
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reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
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be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Impairment of Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm parameters and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
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Figure 1 graph
The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
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For current labeling information, please visit https://www.fda.gov/drugsatfda
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
graph
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
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17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
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driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
Multiorgan Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium delayed release capsules)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
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Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
◦ nausea or vomiting that does not go away
◦ loss of appetite
◦ pain on the right side of your stomach (abdomen)
◦ dark urine
◦ swelling of your face
◦ yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
◦ If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects that affect the brain and spinal cord and are called
spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies
born to mothers who use this medicine during pregnancy. These defects can begin in the
first month, even before you know you are pregnant. Other birth defects that affect the
structures of the heart, head, arms, legs, and the opening where the urine comes out
(urethra) on the bottom of the penis can also happen.
◦ Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
◦ Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
◦ If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
◦ There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
◦ Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
◦ All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
◦ Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
◦ Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
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Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
◦ thoughts about suicide or dying
◦ attempts to commit suicide
◦ new or worse depression
◦ new or worse anxiety
◦ feeling agitated or restless
◦ panic attacks
◦ trouble sleeping (insomnia)
◦ new or worse irritability
◦ acting aggressive, being angry, or violent
◦ acting on dangerous impulses
◦ an extreme increase in activity and talking (mania)
◦ other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
◦ Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
◦ Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
◦ complex partial seizures in adults and children 10 years of age and older
◦ simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
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• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you cannot swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
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See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your
joints due to bleeding or bleeding from your mouth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
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• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
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250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: February 2016
03-B302
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|
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018081s064,018082s047lbl.pdf', 'application_number': 18082, 'submission_type': 'SUPPL ', 'submission_number': 47}
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1
TOLECTIN® DS
(tolmetin sodium)
Capsules
TOLECTIN® 600
(tolmetin sodium)
Tablets
For Oral Administration
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk may
increase with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk. (See WARNINGS.)
• TOLECTIN is contraindicated for the treatment of peri-operative pain in the
setting
of
coronary
artery
bypass
graft
(CABG)
surgery
(see
CONTRAINDICATIONS and WARNINGS.).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or intestines,
which can be fatal. These events can occur at any time during use and without
warning symptoms. Elderly patients are at greater risk for serious
gastrointestinal events. (See WARNINGS.)
DESCRIPTION
TOLECTIN DS (tolmetin sodium) capsules for oral administration contain tolmetin
sodium as the dihydrate in an amount equivalent to 400 mg of tolmetin. Each capsule
contains 36 mg (1.568 mEq) of sodium and the following inactive ingredients:
gelatin, magnesium stearate, corn starch, talc, FD&C Red No. 3, FD&C Yellow No.
6 and titanium dioxide.
TOLECTIN 600 (tolmetin sodium) tablets for oral administration contain tolmetin
sodium as the dihydrate in an amount equivalent to 600 mg of tolmetin. Each tablet
contains 54 mg (2.35 mEq) of sodium and the following inactive ingredients:
cellulose, silicon dioxide, crospovidone, hydroxypropyl methyl cellulose, magnesium
stearate, polyethylene glycol, corn starch, titanium dioxide, FD&C Yellow No. 6 and
D&C Yellow No. 10.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
The pKa of tolmetin is 3.5 and tolmetin sodium is freely soluble in water.
Tolmetin sodium is a nonselective nonsteroidal anti-inflammatory agent. The
structural formula is:
Sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate.
CLINICAL PHARMACOLOGY
Studies in animals have shown TOLECTIN (tolmetin sodium) to possess
anti-inflammatory, analgesic, and antipyretic activity. In the rat, TOLECTIN prevents
the development of experimentally induced polyarthritis and also decreases
established inflammation.
The mode of action for TOLECTIN is not known. However, studies in laboratory
animals and man have demonstrated that the anti-inflammatory action of TOLECTIN
is not due to pituitary-adrenal stimulation. TOLECTIN inhibits prostaglandin
synthetase in vitro and lowers the plasma level of prostaglandin E in man. This
reduction in prostaglandin synthesis may be responsible for the anti-inflammatory
action. TOLECTIN does not appear to alter the course of the underlying disease in
man.
In patients with rheumatoid arthritis and in normal volunteers, tolmetin sodium is
rapidly and almost completely absorbed with peak plasma levels being reached within
30-60 minutes after an oral therapeutic dose. In controlled studies, the time to reach
peak tolmetin plasma concentration is approximately 20 minutes longer following
administration of a 600 mg tablet, compared to an equivalent dose given as 200 mg
tablets. The clinical meaningfulness of this finding, if any, is unknown. Tolmetin
displays a biphasic elimination from the plasma consisting of a rapid phase with a
half-life of 1 to 2 hours followed by a slower phase with a half-life of about 5 hours.
Peak plasma levels of approximately 40 µg/mL are obtained with a 400 mg oral dose.
Essentially all of the administered dose is recovered in the urine in 24 hours either as
an inactive oxidative metabolite or as conjugates of tolmetin. An 18-day multiple
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3
dose study demonstrated no accumulation of tolmetin when compared with a single
dose.
In two fecal blood loss studies of 4 to 6 days duration involving 15 subjects each,
TOLECTIN did not induce an increase in blood loss over that observed during a
4-day drug-free control period. In the same studies, aspirin produced a greater blood
loss than occurred during the drug-free control period, and a greater blood loss than
occurred during the TOLECTIN treatment period. In one of the two studies,
indomethacin produced a greater fecal blood loss than occurred during the drug-free
control period; in the second study, indomethacin did not induce a significant increase
in blood loss.
TOLECTIN is effective in treating both the acute flares and in the long-term
management of the symptoms of rheumatoid arthritis, osteoarthritis and juvenile
rheumatoid arthritis.
In patients with either rheumatoid arthritis or osteoarthritis, TOLECTIN is as
effective as aspirin and indomethacin in controlling disease activity, but the frequency
of the milder gastrointestinal adverse effects and tinnitus was less than in
aspirin-treated patients, and the incidence of central nervous system adverse effects
was less than in indomethacin-treated patients.
In patients with juvenile rheumatoid arthritis, TOLECTIN is as effective as aspirin in
controlling disease activity, with a similar incidence of adverse reactions. Mean
SGOT values, initially elevated in patients on previous aspirin therapy, remained
elevated in the aspirin group and decreased in the TOLECTIN group.
TOLECTIN has produced additional therapeutic benefit when added to a regimen of
gold salts and, to a lesser extent, with corticosteroids. TOLECTIN should not be used
in conjunction with salicylates since greater benefit from the combination is not
likely, but the potential for adverse reactions is increased.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of TOLECTIN and other treatment
options before deciding to use TOLECTIN. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (see
WARNINGS).
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4
TOLECTIN (tolmetin sodium) is indicated for the relief of signs and symptoms of
rheumatoid arthritis and osteoarthritis. TOLECTIN is indicated in the treatment of
acute flares and the long-term management of the chronic disease.
TOLECTIN is also indicated for treatment of juvenile rheumatoid arthritis. The safety
and effectiveness of TOLECTIN have not been established in pediatric patients under
2 years of age (see PRECAUTIONS: Pediatric Use and DOSAGE AND
ADMINSTRATION).
CONTRAINDICATIONS
TOLECTIN is contraindicated in patients with known hypersensitivity to tolmetin
sodium.
TOLECTIN should not be given to patients who have experienced asthma, urticaria
or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal,
anaphylactic-like reactions to NSAIDs have been reported in such patients (see
WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting
Asthma).
TOLECTIN is contraindicated for the treatment of peri-operative pain in the setting
of coronary artery bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
Cardiovascular Effects
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDS of up to three
years duration have shown an increased risk of serious cardiovascular (CV)
thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs,
both COX-2 selective and nonselective, may have a similar risk. Patients with known
CV disease or risk factors for CV disease may be at greater risk. To minimize the
potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and
patients should remain alert for the development of such events, even in the absence
of previous CV symptoms. Patients should be informed about the signs and/or
symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased
risk of serious CV thrombotic events associated with NSAID use. The concurrent use
of aspirin and an NSAID does increase the risk of serious GI events (see
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5
WARNINGS: Gastrointestinal (GI) Effects—Risk of Ulceration, Bleeding, and
Perforation).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of
pain in the first 10 to 14 days following CABG surgery found an increased incidence
of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including TOLECTIN, can lead to onset of new hypertension or worsening
of preexisting hypertension, either of which may contribute to the increased incidence
of CV events. Patients taking thiazides or loop diuretics may have impaired response
to these therapies when taking NSAIDs. NSAIDs, including TOLECTIN, should be
used with caution in patients with hypertension. Blood pressure (BP) should be
monitored closely during the initiation of NSAID treatment and throughout the course
of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs.
TOLECTIN should be used with caution in patients with fluid retention or heart
failure.
Gastrointestinal (GI) Effects—Risk of Ulceration, Bleeding, and
Perforation
NSAIDs, including TOLECTIN, can cause serious gastrointestinal adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach, small
intestine or large intestine, which can be fatal. These serious adverse events can occur
at any time, with or without warning symptoms in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by
NSAIDS occur in approximately 1% of patients treated for 3 to 6 months, and in
about 2 to 4% of patients treated for one year. These trends continue with longer
duration of use, increasing the likelihood of developing a serious GI event at some
time during the course of therapy. However, even short-term therapy is not without
risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of
ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer
disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold
increased risk for developing a GI bleed compared to patients with neither of these
risk factors. Other factors that increase the risk for GI bleeding in patients treated
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6
with NSAIDs include concomitant use of oral corticosteroids or anticoagulants,
longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and, therefore, special care should be taken in treating this
population.
To minimize the potential risk for an adverse GI event in patients treated with an
NSAID, the lowest effective dose should be used for the shortest possible duration.
Patients and physicians should remain alert for signs and symptoms of GI ulceration
and bleeding during NSAID therapy and promptly initiate additional evaluation and
treatment if a serious GI adverse event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-
risk patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and
other renal injury. including reports of aAcute interstitial nephritis with hematuria,
proteinuria, and occasionally nephrotic syndrome have been reported in patients
treated with TOLECTIN. Renal toxicity has also been seen in patients in whom renal
prostaglandins have a compensatory role in the maintenance of renal perfusion. In
these patients, administration of an NSAID may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which may precipitate
overt renal decompensation. Patients at greatest risk of this reaction are those with
impaired renal function, heart failure, liver dysfunction, those taking diuretics and
ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually
followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical trials regarding the use of
TOLECTIN in patients with advanced renal disease. Therefore, treatment with
TOLECTIN is not recommended in these patients with advanced renal disease. If
TOLECTIN therapy must be initiated, close monitoring of the patient’s renal function
is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients with known
prior exposure to TOLECTIN. TOLECTIN should not be given to patients with the
aspirin triad. This symptom complex typically occurs in asthmatic patients who
experience rhinitis with or without nasal polyps, or who exhibit severe, potentially
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7
fatal
bronchospasm
after
taking
aspirin
or
other
NSAIDS
(see
CONTRAINDICATIONS
and
PRECAUTIONS:
Preexisting
Asthma).
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including TOLECTIN, can cause serious skin adverse events such as
exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal
necrolysis (TEN), which can be fatal. These serious events may occur without
warning. Patients should be informed about the signs and symptoms of serious skin
manifestations and use of the drug should be discontinued at the first appearance of
skin rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, TOLECTIN should be avoided because it
may cause premature closure of the ductus arteriosus (see also PRECAUTIONS:
Pregnancy).
PRECAUTIONS
General
TOLECTIN cannot be expected to substitute for corticosteroids or to treat
corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to
disease exacerbation. Patients on prolonged corticosteroid therapy should have their
therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of TOLECTIN in reducing fever and inflammation may
diminish the utility of these diagnostic signs in detecting complications of presumed
noninfectious, painful conditions.
Ophthalmological Effects
Because of ocular changes observed in animals and of reports of adverse eye findings
with NSAIDs, it is recommended that patients who develop visual disturbances
during treatment with TOLECTIN have ophthalmologic evaluations.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients
taking NSAIDs, including TOLECTIN. These laboratory abnormalities may progress,
may remain unchanged, or may be transient with continuing therapy. Notable
elevations of ALT or AST (approximately three or more times the upper limit of
normal) have been reported in approximately 1% of patients in clinical trials with
NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and
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8
fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal
outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an
abnormal liver test has occurred should be evaluated for evidence of the development
of a more severe hepatic reaction while on therapy with TOLECTIN. If clinical signs
and symptoms consistent with liver disease develop, or if systemic manifestations
occur (e.g., eosinophilia, rash, etc.), TOLECTIN should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including TOLECTIN. This
may be due to fluid retention, occult or gross GI blood loss, or an incompletely
described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs,
including TOLECTIN, should have their hemoglobin or hematocrit checked if they
exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and
have been shown to prolong bleeding time in some patients. Unlike aspirin, their
effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving TOLECTIN who may be adversely affected by alterations in
platelet function, such as those with coagulation disorders or patients receiving
anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients
with aspirin-sensitive asthma has been associated with severe bronchospasm which
can be fatal. Since cross reactivity, including bronchospasm, between aspirin and
other NSAIDs has been reported in such aspirin-sensitive patients, TOLECTIN
should not be administered to patients with this form of aspirin sensitivity and should
be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing therapy.
Patients should also be encouraged to read the NSAID Medication Guide that
accompanies each prescription dispensed.
1. TOLECTIN, like other NSAIDs, may cause serious CV side effects, such as
MI or stroke, which may result in hospitalization and even death. Although
serious CV events can occur without warning symptoms, patients should be
alert for the signs and symptoms of chest pain, shortness of breath, weakness,
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9
slurring of speech, and should ask for medical advice when observing any
indicative signs or symptoms. Patients should be apprised of the importance of
this follow-up (see WARNINGS: Cardiovascular Effects).
2. TOLECTIN, like other NSAIDs, can cause GI discomfort and, rarely, serious
GI side effects, such as ulcers and bleeding, which may result in
hospitalization and even death. Although serious GI tract ulcerations and
bleeding can occur without warning symptoms, patients should be alert for the
signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative signs or symptoms including epigastric
pain, dyspepsia, melena, and hematemesis Patients should be apprised of the
importance of this follow-up (see WARNINGS: Gastrointestinal (GI)
Effects—Risk of Ulceration, Bleeding, and Perforation).
3. TOLECTIN, like other NSAIDs, can cause serious skin side effects such as
exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and
even death. Although serious skin reactions may occur without warning,
patients should be alert for the signs and symptoms of skin rash and blisters,
fever, or other signs of hypersensitivity, such as itching, and should ask for
medical advise when observing any indicative signs or symptoms. Patients
should be advised to stop the drug immediately if they develop any type of
rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight
gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper
quadrant tenderness, and “flu-like” symptoms). If these occur, patients should
be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g.,
difficulty breathing, swelling of the face or throat). If these occur, patients
should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, TOLECTIN should be avoided
because it may cause premature closure of the ductus arteriosus.
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10
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning
symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients
on long-term treatment with NSAIDs should have their CBC and a chemistry profile
checked periodically. If clinical signs and symptoms consistent with liver or renal
disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if
abnormal liver tests persist or worsen, TOLECTIN should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs
concomitantly with ACE-inhibitors.
Aspirin
As with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is
not generally recommended because of the potential of increased adverse effects.
Diuretics
Clinical studies, as well as post-marketing observations, have shown that NSAIDs
can reduce the natriuretic effect of furosemide and thiazides in some patients. This
response has been attributed to inhibition of renal prostaglandin synthesis. During
concomitant therapy with NSAIDs, the patient should be observed closely for signs of
renal failure, as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal
lithium clearance. The mean minimum lithium concentration increased 15% and the
renal clearance was decreased by approximately 20%. These effects have been
attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when
NSAIDs and lithium are administered concurrently, subjects should be observed
carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of
methotrexate. Caution should be used when NSAIDs are administered concomitantly
with methotrexate.
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11
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of
both drugs together have a risk of serious GI bleeding higher than users of either drug
alone.
The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin,
and tolmetin does not alter the prothrombin time of normal volunteers. However,
increased prothrombin time and bleeding have been reported in patients on
concomitant TOLECTIN and warfarin therapy. Therefore, caution should be
exercised when administering TOLECTIN to patients on anticoagulants.
Hypoglycemic Agents
In adult diabetic patients under treatment with either sulfonylureas or insulin there is
no change in the clinical effects of either TOLECTIN or the hypoglycemic agents.
Drug/Laboratory Test Interactions
The metabolites of tolmetin sodium in urine have been found to give positive tests for
proteinuria using tests which rely on acid precipitation as their endpoint
(e.g., sulfosalicylic acid). No interference is seen in the tests for proteinuria using
dye-impregnated commercially available reagent strips (e.g., Albustix®, Uristix®,
etc.).
Drug-Food Interactions
In a controlled single-dose study, administration of TOLECTIN with milk had no
effect on peak plasma tolmetin concentrations, but decreased total tolmetin
bioavailability by 16%. When TOLECTIN was taken immediately after a meal, peak
plasma tolmetin concentrations were reduced by 50% while total bioavailability was
again decreased by 16%.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tolmetin sodium did not possess any carcinogenic liability in the following long-term
studies: a 24-month study in rats at doses as high as 75 mg/kg/day, and an 18-month
study in mice at doses as high as 50 mg/kg/day.
No mutagenic potential of tolmetin sodium was found in the Ames
Salmonella-Microsomal Activation Test.
Reproductive studies revealed no impairment of fertility in animals. Effects on
parturition have been shown, however, as with other prostaglandin inhibitors. This
information is detailed in the Pregnancy section.
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12
Pregnancy
Teratogenic Effects: Pregnancy Category C
Reproduction studies in rats and rabbits at doses up to 50 mg/kg (1.5 times the
maximum clinical dose based on a body weight of 60 kg) revealed no evidence of
teratogenesis or impaired fertility due to TOLECTIN. However, animal reproduction
studies are not always predictive of human response. There are no adequate and well-
controlled studies in pregnant women. TOLECTIN should be used in pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of NSAIDs on the fetal cardiovascular system (closure
of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin
synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup
survival occurred. The effects of TOLECTIN on labor and delivery in pregnant
women are unknown.
Nursing Mothers
Tolmetin sodium has been shown to be secreted in human milk. Because of the
potential for serious adverse reactions in nursing infants from tolmetin sodium, a
decision should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 years have not been
established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years
and older).
ADVERSE REACTIONS
The adverse reactions which have been observed in clinical trials encompass
observations in about 4370 patients treated with TOLECTIN (tolmetin sodium), over
800 of whom have undergone at least one year of therapy. These adverse reactions,
reported below by body system, are among those typical of nonsteroidal
anti-inflammatory drugs and, as expected, gastrointestinal complaints were most
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13
frequent. In clinical trials with TOLECTIN, about 10% of patients dropped out
because of adverse reactions, mostly gastrointestinal in nature.
Incidence Greater Than 1%
The following adverse reactions which occurred more frequently than 1 in 100 were
reported in controlled clinical trials.
Gastrointestinal: Nausea (11%), dyspepsia,* gastrointestinal distress,* abdominal
pain,* diarrhea,* flatulence,* vomiting,* constipation, gastritis, and peptic ulcer.
Forty percent of the ulcer patients had a prior history of peptic ulcer disease and/or
were receiving concomitant anti-inflammatory drugs including corticosteroids, which
are known to produce peptic ulceration.
Body as a Whole: Headache, * asthenia, * chest pain
Cardiovascular: Elevated blood pressure, * edema*
Central Nervous System: Dizziness, * drowsiness, depression
Metabolic/Nutritional: Weight gain, * weight loss*
Dermatologic: Skin irritation
Special Senses: Tinnitus, visual disturbance
Hematologic: Small and transient decreases in hemoglobin and hematocrit not
associated with gastrointestinal bleeding have occurred. These are similar to changes
reported with other nonsteroidal anti-inflammatory drugs.
Urogenital: Elevated BUN, urinary tract infection
*Reactions occurring in 3% to 9% of patients treated with TOLECTIN. Reactions
occurring in fewer than 3% of the patients are unmarked.
Incidence Less Than 1%
(Causal Relationship Probable)
The following adverse reactions were reported less frequently than 1 in
100 controlled clinical trials or were reported since marketing. The probability exists
that there is a causal relationship between TOLECTIN and these adverse reactions.
Gastrointestinal: Gastrointestinal bleeding with or without evidence of peptic ulcer,
perforation, glossitis, stomatitis, hepatitis, liver function abnormalities.
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14
Body as a Whole: Anaphylactoid reactions, fever, lymphadenopathy, serum sickness
Hematologic:
Hemolytic
anemia,
thrombocytopenia,
granulocytopenia,
agranulocytosis
Cardiovascular: Congestive heart failure in patients with marginal cardiac function.
Dermatologic: Urticaria, purpura, erythema multiforme, toxic epidermal necrolysis
Urogenital: Hematuria, proteinuria, dysuria, renal failure
Incidence Less Than 1%
(Causal Relationship Unknown)
Other adverse reactions were reported less frequently than 1 in 100 in controlled
clinical trials or were reported since marketing, but a causal relationship between
TOLECTIN and the reaction could not be determined. These rarely reported reactions
are being listed as alerting information for the physician since the possibility of a
causal relationship cannot be excluded.
Body as a Whole: Epistaxis
Special Senses: Optic neuropathy, retinal and macular changes
MANAGEMENT OF OVERDOSAGE
In the event of overdosage, the stomach should be emptied by inducing vomiting or
by gastric lavage followed by the administration of activated charcoal.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of TOLECTIN and other treatment
options before deciding to use TOLECTIN. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (see
WARNINGS).
After observing the response to initial therapy with TOLECTIN, the dose and
frequency should be adjusted to suit an individual patient’s needs.
For the relief of rheumatoid arthritis or osteoarthritis, the recommended starting dose
for adults is 400 mg three times daily (1200 mg daily), preferably including a dose on
arising and a dose at bedtime. To achieve optimal therapeutic effect the dose should
be adjusted according to the patient’s response after one or two weeks. Control is
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15
usually achieved at doses of 600-1800 mg daily in divided doses (generally t.i.d.).
Doses larger than 1800 mg/day have not been studied and are not recommended.
For the relief of juvenile rheumatoid arthritis, the recommended starting dose for
pediatric patients (2 years and older) is 20 mg/kg/day in divided doses (t.i.d. or q.i.d.).
When control has been achieved, the usual dose ranges from 15 to 30 mg/kg/day.
Doses higher than 30 mg/kg/day have not been studied, and, therefore, are not
recommended.
A therapeutic response to TOLECTIN (tolmetin sodium) can be expected in a few
days to a week. Progressive improvement can be anticipated during succeeding weeks
of therapy. If gastrointestinal symptoms occur, TOLECTIN can be administered with
antacids
other
than
sodium
bicarbonate.
TOLECTIN
bioavailability
and
pharmacokinetics are not significantly affected by acute or chronic administration of
magnesium and aluminum hydroxides; however, bioavailability is affected by food or
milk (see PRECAUTIONS: Drug-Food Interaction).
HOW SUPPLIED
TOLECTIN® DS (tolmetin sodium) capsules 400 mg (colored orange opaque with
contrasting parallel bands, imprinted “TOLECTIN DS” and “McNEIL”), NDC
0045-0414, bottles of 100 and 500.
TOLECTIN® 600 (tolmetin sodium) tablets 600 mg (colored orange, film coated,
imprinted “TOLECTIN 600” and “McNEIL”), NDC 0045-0416, bottles of 100 and
500.
Dispense in tight, light-resistant container as defined in the official compendium.
Store at controlled room temperature (15°-30°C, 59°-86°F). Protect from light.
ORTHO-McNEIL logo
OMP DIVISION
ORTHO-McNEIL PHARMACEUTICAL, INC.
Raritan, NJ 08869
Printed in U.S.A.
©OMP 2006
Revised
Month
2006
XXXXXXX
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16
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines
called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke
that can lead to death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart
surgery called a “coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and
intestines at any time during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat
(inflammation) from medical conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
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17
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or
any other NSAID medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can
interact with each other and cause serious side effects. Keep a list of your
medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant
women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid
retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and
intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following
symptoms:
• shortness of breath or trouble
breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your
body
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18
Stop your NSAID medicine and call your healthcare provider right away
if you have any of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and
sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs,
hands and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare
provider or pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart
attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin
can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription
(over-the-counter). Talk to your healthcare provider before using over-the-counter
NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with
hydrocodone), Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan,
Naprapac (copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:35.977821
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017628s067,018084s051lbl.pdf', 'application_number': 18084, 'submission_type': 'SUPPL ', 'submission_number': 51}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid), capsules, USP, for oral use
DEPAKENE (valproic acid) oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
RECENT MAJOR CHANGES
Warnings and Precautions, Birth Defects (5.2)
1/2015
Warnings and Precautions, Bleeding and Other Hematopoietic
Disorders (5.8)
1/2015
Warnings and Precautions, Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reaction
(5.12)
1/2015
INDICATIONS AND USAGE
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence seizures
(1)
DOSAGE AND ADMINISTRATION
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
DOSAGE FORMS AND STRENGTHS
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
CONTRAINDICATIONS
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial DNA
polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
WARNINGS AND PRECAUTIONS
• Hepatotoxicity; evaluate high risk populations and monitor serum liver tests
(5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Bleeding and other hematopoietic disorders; monitor platelet counts and
coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy with
or without associated hyperammonemia. This adverse reaction can also
occur in patients using concomitant topiramate (5.11)
• Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan hypersensitivity reaction; discontinue Depakene
(5.12)
• Somnolence in the elderly can occur. Depakene dosage should be increased
slowly and with regular monitoring for fluid and nutritional intake (5.14)
ADVERSE REACTIONS
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance, while
enzyme inhibitors (e.g., felbamate) can decrease valproate clearance.
Therefore increased monitoring of valproate and concomitant drug
concentrations and dosage adjustment are indicated whenever enzyme-
inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine
may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
USE IN SPECIFIC POPULATIONS
• Pregnancy: Depakene can cause congenital malformations including neural
tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid
and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.8 Bleeding and Other Hematopoietic Disorders
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Post-Marketing Experience
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The
rate of congenital malformations among babies born to mothers using valproate is about four
times higher than the rate among babies born to epileptic mothers using other anti-seizure
monotherapies. Evidence suggests that folic acid supplementation prior to conception and during
the first trimester of pregnancy decreases the risk for congenital neural tube defects in the
general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Bleeding and Other Hematopoietic Disorders
Valproate is associated with dose-related thrombocytopenia. In a clinical trial of Depakote
(divalproex sodium) as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving
approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L.
Approximately half of these patients had treatment discontinued, with return of platelet counts to
normal. In the remaining patients, platelet counts normalized with continued treatment. In this
study, the probability of thrombocytopenia appeared to increase significantly at total valproate
concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit
which may accompany the higher doses should therefore be weighed against the possibility of a
greater incidence of adverse effects. Valproate use has also been associated with decreases in
other cell lines and myelodysplasia.
Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and
abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired
von Willebrand’s disease), measurements of complete blood counts and coagulation tests are
recommended before initiating therapy and at periodic intervals. It is recommended that patients
receiving Depakene (valproic acid) be monitored for blood counts and coagulation parameters
prior to planned surgery and during pregnancy [see Use in Specific Populations (8.1)]. Evidence
of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of
the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
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not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity Reactions
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy, in association with other organ system involvement, such as hepatitis,
nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute
viral infection. Eosinophilia is often present. Because this disorder is variable in its expression,
other organ systems not noted here may be involved. It is important to note that early
manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even
though rash is not evident. If such signs or symptoms are present, the patient should be evaluated
immediately. Valproate should be discontinued and not be resumed if an alternative etiology for
the signs or symptoms cannot be established.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
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higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
• Hepatic failure [see Warnings and Precautions (5.1)]
• Birth defects [see Warnings and Precautions (5.2)]
• Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
• Pancreatitis [see Warnings and Precautions (5.5)]
• Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
• Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
• Hypothermia [see Warnings and Precautions (5.11)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
hypersensitivity reactions [see Warnings and Precautions (5.12)]
• Somnolence in the elderly [see Warnings and Precautions (5.14)]
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Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
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Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
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Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
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6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience
The following adverse reactions have been identified during post approval use of Depakote.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Dermatologic: Hair texture changes, hair color changes, photosensitivity, erythema multiforme,
toxic epidermal necrolysis, and Stevens-Johnson syndrome.
Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility,
disturbance in attention, learning disorder, and behavioral deterioration.
Neurologic: There have been several reports of acute or subacute cognitive decline and
behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated
with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy
reversed partially or fully after valproate discontinuation.
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Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and
weakness.
Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, anemia including macrocytic
with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia,
agranulocytosis, and acute intermittent porphyria.
Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated
testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary
disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate
ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Reproductive: Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility,
male infertility, and abnormal spermatozoa morphology.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss.
Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and
cutaneous vasculitis.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For
example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance
of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher
concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
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metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
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Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co-
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
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In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
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Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
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To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations, hypospadias, limb malformations). The risk of major structural abnormalities is
greatest during the first trimester; however, other serious developmental effects can occur with
valproate use throughout pregnancy. The rate of congenital malformations among babies born to
epileptic mothers who used valproate during pregnancy has been shown to be about four times
higher than the rate among babies born to epileptic mothers who used other anti-seizure
monotherapies [see Warnings and Precautions (5.3)].
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
An observational study has suggested that exposure to valproate products during pregnancy may
increase the risk of autism spectrum disorders. In this study, children born to mothers who had
used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]:
1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not
exposed to valproate products during pregnancy. The absolute risks for autism spectrum
disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI:
1.5%-1.6%) in children not exposed to valproate products. Because the study was observational
in nature, conclusions regarding a causal association between in utero valproate exposure and an
increased risk of autism spectrum disorder cannot be considered definitive.
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
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• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Pregnant women taking valproate may develop clotting abnormalities including
thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which
may result in hemorrhagic complications in the neonate including death [see Warnings and
Precautions (5.8)]. If valproate is used in pregnancy, the clotting parameters should be
monitored carefully in the mother. If abnormal in the mother, then these parameters should
also be monitored in the neonate.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
• Hypoglycemia has been reported in neonates whose mothers have taken valproate during
pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the
offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during
pregnancy. These data show up to a five-fold increased risk for any major malformation
following valproate exposure in utero compared to the risk following exposure in utero to other
antiepileptic drugs taken in monotherapy. The major congenital malformations included cases of
neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts,
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craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and
malformations of varying severity involving other body systems.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
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patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
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these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, deep coma, and
hypernatremia. Fatalities have been reported; however, patients have recovered from valproate
levels as high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
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Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
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Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Impairment of Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm parameters and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-
2334 [see Use in Specific Populations (8.1)].
Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
Multiorgan Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium delayed release capsules)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
◦ nausea or vomiting that does not go away
◦ loss of appetite
◦ pain on the right side of your stomach (abdomen)
◦ dark urine
◦ swelling of your face
◦ yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
◦ If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects that affect the brain and spinal cord and are called
spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies
born to mothers who use this medicine during pregnancy. These defects can begin in the
first month, even before you know you are pregnant. Other birth defects that affect the
structures of the heart, head, arms, legs, and the opening where the urine comes out
(urethra) on the bottom of the penis can also happen.
◦ Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
◦ Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
◦ If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
◦ There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
◦ Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
◦ All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
◦ Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
◦ Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
◦ thoughts about suicide or dying
◦ attempts to commit suicide
◦ new or worse depression
◦ new or worse anxiety
◦ feeling agitated or restless
◦ panic attacks
◦ trouble sleeping (insomnia)
◦ new or worse irritability
◦ acting aggressive, being angry, or violent
◦ acting on dangerous impulses
◦ an extreme increase in activity and talking (mania)
◦ other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
◦ Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
◦ Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
◦ complex partial seizures in adults and children 10 years of age and older
◦ simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you cannot swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your
joints due to bleeding or bleeding from your mouth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: September 2015
03-B210
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Depakote ER safely and effectively. See full prescribing information for
Depakote ER.
Depakote ER (divalproex sodium) Tablet, Extended Release for Oral use
Initial U.S. Approval: 2000
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Contraindications, Prophylaxis of Migraines in Pregnancy (4) 06/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
Warning and Precautions, Medication Residue in the Stool (5.18) 02/2013
-------INDICATIONS AND USAGE-------
Depakote ER is an anti-epileptic drug indicated for:
• Acute treatment of manic or mixed episodes associated with bipolar
disorder, with or without psychotic features (1.1)
• Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence seizures; adjunctive therapy in patients with
multiple seizure types that include absence seizures (1.2)
• Prophylaxis of migraine headaches (1.3)
-------DOSAGE AND ADMINISTRATION-------
• Depakote ER is intended for once-a-day oral administration. Depakote ER
should be swallowed whole and should not be crushed or chewed (2.1,
2.2).
• Mania: Initial dose is 25 mg/kg/day, increasing as rapidly as possible to
achieve therapeutic response or desired plasma level (2.1). The maximum
recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1
week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response;
if response is not satisfactory, check valproate plasma level; see full
prescribing information for conversion to monotherapy (2.2). The
maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by
5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The
maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Migraine: The recommended starting dose is 500 mg/day for 1 week,
thereafter increasing to 1000 mg/day (2.3).
-------DOSAGE FORMS AND STRENGTHS-------
Tablets: 250 mg and 500 mg (3)
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
• Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy or bipolar disorder if other
medications are unacceptable; should not be administered to a woman of
childbearing potential unless essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakote ER should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakote ER,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status, and also with concomitant topiramate use; consider discontinuation
of valproate therapy (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakote ER (5.12)
• Somnolence in the elderly can occur. Depakote ER dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) reported in adult studies
are nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain,
dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back
pain, alopecia, headache, fever, anorexia, constipation, diplopia,
amblyopia/blurred, ataxia, nystagmus, emotional lability, thinking
abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis,
ecchymosis, peripheral edema, insomnia, nervousness, depression,
pharyngitis, dyspnea, tinnitus (6.1, 6.2, 6.3, 6.4).
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
primidone, phenobarbital, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dose adjustment is indicated whenever enzyme-
inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations
are recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakote ER
(7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakote ER can cause congenital malformations including
neural tube defects and decreased IQ. (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1.1 Mania
1 INDICATIONS AND USAGE
1.2 Epilepsy
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1.3 Migraine
1.4 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Mania
2.2 Epilepsy
2.3 Migraine
2.4 Conversion from Depakote to Depakote ER
2.5 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
5.18 Medication Residue in the Stool
6 ADVERSE REACTIONS
6.1 Mania
6.2 Epilepsy
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Effect of Disease
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Mania
14.2 Epilepsy
14.3 Migraine
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-organ Hypersensitivity Reaction
17.8 Medication Residue in the Stool
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate and its derivatives. These incidents usually have occurred during the first six
months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In
patients with epilepsy, a loss of seizure control may also occur. Patients should be
monitored closely for appearance of these symptoms. Serum liver tests should be
performed prior to therapy and at frequent intervals thereafter, especially during the first
six months [see Warnings and Precautions (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakote ER is used in this
patient group, it should be used with extreme caution and as a sole agent. The benefits of
therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases
considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakote ER is contraindicated in patients known to
have mitochondrial disorders caused by POLG mutations and children under two years of
age who are clinically suspected of having a mitochondrial disorder [see Contraindications
(4)]. In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote ER should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakote ER for the development of acute liver injury with regular clinical assessments
and serum liver testing. POLG mutation screening should be performed in accordance
with current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate is therefore contraindicated in pregnant women treated for prophylaxis of
migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant
women with epilepsy or bipolar disorder if other medications have failed to control their
symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
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is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Mania
Depakote ER is a valproate and is indicated for the treatment of acute manic or mixed episodes
associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct
period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms
of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas,
grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is
characterized by the criteria for a manic episode in conjunction with those for a major depressive
episode (depressed mood, loss of interest or pleasure in nearly all activities).
The efficacy of Depakote ER is based in part on studies of Depakote (divalproex sodium delayed
release tablets) in this indication, and was confirmed in a 3-week trial with patients meeting
DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute
mania [see Clinical Studies (14.1)].
The effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been
demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use
Depakote ER for extended periods should continually reevaluate the long-term risk-benefits of
the drug for the individual patient.
1.2 Epilepsy
Depakote ER is indicated as monotherapy and adjunctive therapy in the treatment of adult
patients and pediatric patients down to the age of 10 years with complex partial seizures that
occur either in isolation or in association with other types of seizures. Depakote ER is also
indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence
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seizures in adults and children 10 years of age or older, and adjunctively in adults and children
10 years of age or older with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
1.3 Migraine
Depakote ER is indicated for prophylaxis of migraine headaches. There is no evidence that
Depakote ER is useful in the acute treatment of migraine headaches.
1.4 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
Depakote ER is contraindicated for prophylaxis of migraine headaches in women who are
pregnant.
2 DOSAGE AND ADMINISTRATION
Depakote ER is an extended-release product intended for once-a-day oral administration.
Depakote ER tablets should be swallowed whole and should not be crushed or chewed.
2.1 Mania
Depakote ER tablets are administered orally. The recommended initial dose is 25 mg/kg/day
given once daily. The dose should be increased as rapidly as possible to achieve the lowest
therapeutic dose which produces the desired clinical effect or the desired range of plasma
concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were
dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL.
The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer
term management of a patient who improves during Depakote ER treatment of an acute manic
episode. While it is generally agreed that pharmacological treatment beyond an acute response in
mania is desirable, both for maintenance of the initial response and for prevention of new manic
episodes, there are no data to support the benefits of Depakote ER in such longer-term treatment
(i.e., beyond 3 weeks).
2.2 Epilepsy
Depakote ER (divalproex sodium) extended release tablets are administered orally, and must be
swallowed whole. As Depakote ER dosage is titrated upward, concentrations of clonazepam,
diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or
phenytoin may be affected [see Drug Interactions (7.2)].
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Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote ER has not been systematically studied as initial therapy. Patients should initiate
therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to
achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses
below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels
should be measured to determine whether or not they are in the usually accepted therapeutic
range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses
above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50 - 100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25%
every 2 weeks. This reduction may be started at initiation of Depakote ER therapy, or delayed by
1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and
duration of withdrawal of the concomitant AED can be highly variable, and patients should be
monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote ER may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The
dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or
phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may
interact with these or other concurrently administered AEDs as well as other drugs, periodic
plasma concentration determinations of concomitant AEDs are recommended during the early
course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
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The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As Depakote ER dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
2.3 Migraine
Depakote ER is indicated for prophylaxis of migraine headaches in adults.
The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000
mg once daily. Although doses other than 1000 mg once daily of Depakote ER have not been
evaluated in patients with migraine, the effective dose range of Depakote (divalproex sodium
delayed-release tablets) in these patients is 500-1000 mg/day. As with other valproate products,
doses of Depakote ER should be individualized and dose adjustment may be necessary. If a
patient requires smaller dose adjustments than that available with Depakote ER, Depakote should
be used instead.
2.4 Conversion from Depakote to Depakote ER
In adult patients and pediatric patients 10 years of age or older with epilepsy previously
receiving Depakote, Depakote ER should be administered once-daily using a dose 8 to 20%
higher than the total daily dose of Depakote (Table 1). For patients whose Depakote total daily
dose cannot be directly converted to Depakote ER, consideration may be given at the clinician’s
discretion to increase the patient’s Depakote total daily dose to the next higher dosage before
converting to the appropriate total daily dose of Depakote ER.
Table 1. Dose Conversion
Depakote
Depakote ER
Total Daily Dose (mg)
(mg)
500* - 625
750
750* - 875
1000
1000*-1125
1250
1250-1375
1500
1500-1625
1750
1750
2000
1875-2000
2250
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2125-2250
2500
2375
2750
2500-2750
3000
2875
3250
3000-3125
3500
* These total daily doses of Depakote cannot be directly converted to an 8 to 20% higher total
daily dose of Depakote ER because the required dosing strengths of Depakote ER are not
available. Consideration may be given at the clinician's discretion to increase the patient's
Depakote total daily dose to the next higher dosage before converting to the appropriate total
daily dose of Depakote ER.
There is insufficient data to allow a conversion factor recommendation for patients with
DEPAKOTE doses above 3125 mg/day. Plasma valproate Cmin concentrations for DEPAKOTE
ER on average are equivalent to DEPAKOTE, but may vary across patients after conversion. If
satisfactory clinical response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL)
[see Clinical Pharmacology (12.2)].
2.5 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in
the elderly lower than 250 mg can only be achieved by the use of Depakote. Dosage should be
increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration,
somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should
be considered in patients with decreased food or fluid intake and in patients with excessive
somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability
and clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5)
and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
Compliance
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Patients should be informed to take Depakote ER every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
3 DOSAGE FORMS AND STRENGTHS
Depakote ER 250 mg is available as white ovaloid tablets with the “a” logo and the code (HF).
Each Depakote ER tablet contains divalproex sodium equivalent to 250 mg of valproic acid.
Depakote ER 500 mg is available as gray ovaloid tablets with the “a” logo and the code HC.
Each Depakote ER tablet contains divalproex sodium equivalent to 500 mg of valproic acid.
4 CONTRAINDICATIONS
• Depakote ER should not be administered to patients with hepatic disease or significant
hepatic dysfunction [see Warnings and Precautions (5.1)].
• Depakote ER is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakote ER is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakote ER is contraindicated in patients with known urea cycle disorders [see Warnings
and Precautions (5.6)].
• Depakote ER is contraindicated for use in prophylaxis of migraine headaches in pregnant
women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
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those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakote ER is used in this patient group, it should be used with extreme caution and as a
sole agent. The benefits of therapy should be weighed against the risks. In progressively older
patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity
decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakote ER is contraindicated in patients known to have mitochondrial disorders caused by
POLG mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote ER should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakote ER for
the development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
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5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]),
carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of
migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to
become pregnant should not be treated with valproate unless other treatments have failed to
provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
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5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, Depakote ER should ordinarily
be discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders
Depakote ER is contraindicated in patients with known urea cycle disorders (UCD).
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
Depakote ER therapy, evaluation for UCD should be considered in the following patients: 1)
those with a history of unexplained encephalopathy or coma, encephalopathy associated with a
protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation,
or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and
lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a
family history of UCD or a family history of unexplained infant deaths (particularly males); 4)
those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakote ER, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
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The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo
Patients with
Events Per
1000 Patients
Drug Patients
with Events
Per 1000
Patients
Relative Risk: Incidence of
Events in Drug
Patients/Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients with Events
Per 1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakote ER or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy,
34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value
of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with
return of platelet counts to normal. In the remaining patients, platelet counts normalized with
continued treatment. In this study, the probability of thrombocytopenia appeared to increase
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significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL
(males). The therapeutic benefit which may accompany the higher doses should therefore be
weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakote ER be monitored for platelet count and
coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder
of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
During the placebo controlled pediatric mania trial, one (1) in twenty (20) adolescents (5%)
treated with valproate developed increased plasma ammonia levels compared to no (0) patients
treated with placebo.
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not
due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
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5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
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nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.4)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
5.18 Medication Residue in the Stool
There have been rare reports of medication residue in the stool. Some patients have had anatomic
(including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI
transit times. In some reports, medication residues have occurred in the context of diarrhea. It is
recommended that plasma valproate levels be checked in patients who experience medication
residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated,
alternative treatment may be considered.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
Information on pediatric adverse reactions is presented in section 8.
6.1 Mania
The incidence of treatment-emergent events has been ascertained based on combined data from
two three week placebo-controlled clinical trials of Depakote ER in the treatment of manic
episodes associated with bipolar disorder.
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Table 3 summarizes those adverse reactions reported for patients in these trials where the
incidence rate in the Depakote ER-treated group was greater than 5% and greater than the
placebo incidence.
Table 3. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During
Placebo-Controlled Trials of Acute Mania1
Adverse Event
Depakote ER
(n=338)
Placebo
(n=263)
Somnolence
26%
14%
Dyspepsia
23%
11%
Nausea
19%
13%
Vomiting
13%
5%
Diarrhea
12%
8%
Dizziness
12%
7%
Pain
11%
10%
Abdominal pain
10%
5%
Accidental injury
6%
5%
Asthenia
6%
5%
Pharyngitis
6%
5%
1. The following adverse reactions/event occurred at an equal or greater incidence for placebo
than for Depakote ER: headache
The following additional adverse reactions were reported by greater than 1% but not more than
5% of the Depakote ER-treated patients in controlled clinical trials:
Body as a Whole: Back Pain, Flu Syndrome, Infection, Infection Fungal
Cardiovascular System: Hypertension
Digestive System: Constipation, Dry Mouth, Flatulence
Hemic and Lymphatic System: Ecchymosis
Metabolic and Nutritional Disorders: Peripheral Edema
Musculoskeletal System: Myalgia
Nervous System: Abnormal Gait, Hypertonia, Tremor
Respiratory System: Rhinitis
Skin and Appendages: Pruritus, Rash
Special Senses: Conjunctivitis
Urogenital System: Urinary Tract Infection, Vaginitis
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6.2 Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in the
placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to
determine whether the following adverse reactions can be ascribed to Depakote alone, or the
combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients Treated with Valproate During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Event
Depakote (%)
(N=77)
Placebo (%)
(N=70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
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Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 5 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose valproate group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
Table 5. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1
Body System/Event
High Dose (%)
(n=131)
Low Dose (%)
(n=134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
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Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1. Headache was the only adverse event that occurred in ≥5% of patients in the high dose group
and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.3 Migraine
Based on two placebo-controlled clinical trials and their long term extension, valproate was
generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the
202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for
intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term
extension study, the adverse reactions reported as the primary reason for discontinuation by ≥
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1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight
gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression
(1%).
Table 6 includes those adverse reactions reported for patients in the placebo-controlled trial
where the incidence rate in the Depakote ER-treated group was greater than 5% and was greater
than that for placebo patients.
Table 6. Adverse Reactions Reported by >5% of Depakote ER-Treated Patients During the
Migraine Placebo-Controlled Trial with a Greater Incidence than Patients Taking Placebo1
Body System
Event
Depakote ER
(n=122)
Placebo
(n=115)
Gastrointestinal System
Nausea
15%
9%
Dyspepsia
7%
4%
Diarrhea
7%
3%
Vomiting
7%
2%
Abdominal Pain
7%
5%
Nervous System
Somnolence
7%
2%
Other
Infection
15%
14%
1. The following adverse reactions occurred in greater than 5% of Depakote ER-treated patients
and at a greater incidence for placebo than for Depakote ER: asthenia and flu syndrome.
The following additional adverse reactions were reported by greater than 1% but not more than
5% of Depakote ER-treated patients and with a greater incidence than placebo in the placebo-
controlled clinical trial for migraine prophylaxis:
Body as a Whole: Accidental injury, viral infection.
Digestive System: Increased appetite, tooth disorder.
Metabolic and Nutritional Disorders: Edema, weight gain.
Nervous System: Abnormal gait, dizziness, hypertonia, insomnia, nervousness, tremor, vertigo.
Respiratory System: Pharyngitis, rhinitis.
Skin and Appendages: Rash.
Special Senses: Tinnitus.
Table 7 includes those adverse reactions reported for patients in the placebo-controlled trials
where the incidence rate in the valproate-treated group was greater than 5% and was greater than
that for placebo patients.
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Table 7. Adverse Reactions Reported by > 5% of Valproate-Treated Patients During
Migraine Placebo-Controlled Trials with a Greater Incidence than Patients Taking
Placebo1
Body System
Reaction
Depakote
(n=202)
Placebo
(n=81)
Gastrointestinal System
Nausea
31%
10%
Dyspepsia
13%
9%
Diarrhea
12%
7%
Vomiting
11%
1%
Abdominal pain
9%
4%
Increased appetite
6%
4%
Nervous System
Asthenia
20%
9%
Somnolence
17%
5%
Dizziness
12%
6%
Tremor
9%
0%
Other
Weight gain
8%
2%
Back pain
8%
6%
Alopecia
7%
1%
1. The following adverse reactions occurred in greater than 5% of Depakote-treated patients and
at a greater incidence for placebo than for Depakote: flu syndrome and pharyngitis.
The following additional adverse reactions were reported by greater than 1% but not more than
5% of the 202 valproate-treated patients in the controlled clinical trials:
Body as a Whole: Chest pain.
Cardiovascular System: Vasodilatation.
Digestive System: Constipation, dry mouth, flatulence, and stomatitis.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Peripheral edema.
Musculoskeletal System: Leg cramps.
Nervous System: Abnormal dreams, confusion, paresthesia, speech disorder, and thinking
abnormalities.
Respiratory System: Dyspnea, and sinusitis.
Skin and Appendages: Pruritus.
Urogenital System: Metrorrhagia.
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6.4 Other Patient Populations
Mania
The following adverse reactions not listed previously were reported by greater than 1% of
Depakote-treated patients and with a greater incidence than placebo in placebo-controlled trials
of manic episodes associated with bipolar disorder:
Body as a Whole: Chills, chills and fever, drug level increased, neck rigidity.
Cardiovascular System: Arrhythmia, hypotension, postural hypotension.
Digestive System: Dysphagia, fecal incontinence, gastroenteritis, glossitis, gum hemorrhage,
mouth ulceration.
Hemic and Lymphatic System: Anemia, bleeding time increased, leucopenia.
Metabolic and Nutritional Disorders: Hypoproteinemia.
Musculoskeletal System: Arthrosis.
Nervous System: Agitation, catatonic reaction, dysarthria, hallucinations, hypokinesia,
psychosis, reflexes increased, sleep disorder, tardive dyskinesia.
Respiratory System: Hiccup.
Skin and Appendages: Discoid lupus erythematosus, erythema nodosum, furunculosis,
maculopapular rash, seborrhea, sweating, vesiculobullous rash.
Special Senses: Conjunctivitis, dry eyes, eye disorder, eye pain, photophobia, taste perversion.
Urogenital System: Cystitis, menstrual disorder.
Epilepsy
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal
The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and
indigestion. These effects are usually transient and rarely require discontinuation of therapy.
Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some
weight loss and increased appetite with weight gain have also been reported. The administration
of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in
some patients.
CNS Effects
Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
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the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic
Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported
including a fatal case in a 6 month old infant taking valproate and several other concomitant
medications. An additional case of toxic epidermal necrosis resulting in death was reported in a
35 year old patient with AIDS taking several concomitant medications and with a history of
multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant
administration of lamotrigine and valproate [see Drug Interactions (7.2)].
Psychiatric
Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal
Weakness.
Hematologic
Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected
in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank
hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic
Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to
be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and
abnormal changes in other liver function tests. These results may reflect potentially serious
hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine
Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic
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Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].
Metabolic
Hyperammonemia [see Warnings and Precautions (5.9, 5.10)], hyponatremia, and inappropriate
ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary
Enuresis and urinary tract infection.
Special Senses
Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other
Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia
[see Warnings and Precautions (5.11)].
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
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The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Whether or not the interaction observed in this
study applies to adults is unknown, but caution should be observed if valproate and aspirin are to
be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
in not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
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A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronosyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
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Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by
a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance
as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially
along with other anticonvulsants, should be monitored for alterations in serum concentrations of
both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase
in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The
fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
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In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n=11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder
[see Warnings and Precautions (5.2, 5.3)].
Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakote, physicians should
encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must
be done by the patients themselves. Information on the registry can be found at the website,
http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
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• Valproate is contraindicated during pregnancy in women being treated for prophylaxis of
migraine headaches.
• Valproate should not be used to treat women with epilepsy or bipolar disorder who are
pregnant or who plan to become pregnant unless other treatments have failed to provide
adequate symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks. When treating a
pregnant woman or a woman of childbearing potential, carefully consider both the
potential risks and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
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mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I.
104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in
this patient group, it should be used with extreme caution and as a sole agent. The benefits of
therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
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indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older
patient groups.
Younger children, especially those receiving enzyme inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentration. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were
shown to be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was
occasionally associated with the latter two events. It is not clear whether these events indicate
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additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.5)].
There is insufficient information available to discern the safety and effectiveness of valproate for
the prophylaxis of migraines in patients over 65.
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26 years) [see Clinical
Pharmacology (12.3)].
8.6 Effect of Disease
Liver Disease
[(See Boxed Warning, Contraindications (4), Warnings and Precautions (5), and Clinical
Pharmacology (12.3)]. Liver disease impairs the capacity to eliminate valproate.
10 OVERDOSAGE
Over dosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and
valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic
acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen
bis(2-propylpentanoate). Divalproex sodium has the following structure:
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Divalproex sodium occurs as a white powder with a characteristic odor.
Depakote ER 250 and 500 mg tablets are for oral administration. Depakote ER tablets contain
divalproex sodium in a once-a-day extended-release formulation equivalent to 250 and 500 mg
of valproic acid.
Inactive Ingredients
Depakote ER 250 and 500 mg tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin.
In addition, 500 mg tablets contain iron oxide and polydextrose.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms
by which valproate exerts its therapeutic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate may not
provide a reliable index of the bioactive valproate species.
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For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total
valproate, although some patients may be controlled with lower or higher plasma concentrations.
Mania
In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with
trough plasma concentrations between 85 and 125 mcg/mL [see Dosage and Administration
(2.1)].
12.3 Pharmacokinetics
Absorption/Bioavailability
The absolute bioavailability of Depakote ER tablets administered as a single dose after a meal
was approximately 90% relative to intravenous infusion.
When given in equal total daily doses, the bioavailability of Depakote ER is less than that of
Depakote (divalproex sodium delayed-release tablets). In five multiple-dose studies in healthy
subjects (N=82) and in subjects with epilepsy (N=86), when administered under fasting and
nonfasting conditions, Depakote ER given once daily produced an average bioavailability of
89% relative to an equal total daily dose of Depakote given BID, TID, or QID. The median time
to maximum plasma valproate concentrations (Cmax) after Depakote ER administration ranged
from 4 to 17 hours. After multiple once-daily dosing of Depakote ER, the peak-to-trough
fluctuation in plasma valproate concentrations was 10-20% lower than that of regular Depakote
given BID, TID, or QID.
Conversion from Depakote to Depakote ER
When Depakote ER is given in doses 8 to 20% higher than the total daily dose of Depakote, the
two formulations are bioequivalent. In two randomized, crossover studies, multiple daily doses
of Depakote were compared to 8 to 20% higher once-daily doses of Depakote ER. In these two
studies, Depakote ER and Depakote regimens were equivalent with respect to area under the
curve (AUC; a measure of the extent of bioavailability). Additionally, valproate Cmax was lower,
and Cmin was either higher or not different, for Depakote ER relative to Depakote regimens (see
Table 9).
Table 9. Bioavailability of Depakote ER Tablets Relative to Depakote When Depakote ER
Dose is 8 to 20% Higher
Study Population
Regimens
Relative Bioavailability
Depakote ER vs.
Depakote
AUC24
Cmax
Cmin
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Healthy Volunteers
(N=35)
1000 & 1500 mg
Depakote ER vs.
875 & 1250 mg
Depakote
1.059
0.882
1.173
Patients with
epilepsy on
concomitant enzyme-
inducing antiepilepsy
drugs (N = 64)
1000 to 5000 mg
Depakote ER vs.
875 to 4250 mg
Depakote
1.008
0.899
1.022
Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and
lamotrigine were evaluated) that induce the cytochrome P450 isozyme system did not
significantly alter valproate bioavailability when converting between Depakote and Depakote
ER.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide)
[see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions
of valproate with other drugs].
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
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The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Pediatric
The valproate pharmacokinetic profile following administration of Depakote ER was
characterized in a multiple-dose, non-fasting, open label, multi-center study in children and
adolescents. Depakote ER once daily doses ranged from 250-1750 mg. Once daily administration
of Depakote ER in pediatric patients (10-17 years) produced plasma VPA concentration-time
profiles similar to those that have been observed in adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.4)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free
valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute
hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and
larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed
Warning, Contraindications (4), and Warnings and Precautions (5.1)].
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
Reference ID: 3520933
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
14.1 Mania
The effectiveness of Depakote ER for the treatment of acute mania is based in part on studies
establishing the effectiveness of Depakote (divalproex sodium delayed release tablets) for this
indication. Depakote ER’s effectiveness was confirmed in one randomized, double-blind,
placebo-controlled, parallel group, 3-week, multicenter study. The study was designed to
evaluate the safety and efficacy of Depakote ER in the treatment of bipolar I disorder, manic or
mixed type, in adults. Adult male and female patients who had a current DSM-IV TR primary
diagnosis of bipolar I disorder, manic or mixed type, and who were hospitalized for acute mania,
were enrolled into this study. Depakote ER was initiated at a dose of 25 mg/kg/day given once
daily, increased by 500 mg/day on Day 3, then adjusted to achieve plasma valproate
concentrations in the range of 85-125 mcg/mL. Mean daily Depakote ER doses for observed
cases were 2362 mg (range: 500-4000), 2874 mg (range: 1500-4500), 2993 mg (range: 1500
4500), 3181 mg (range: 1500-5000), and 3353 mg (range: 1500-5500) at Days 1, 5, 10, 15, and
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21, respectively. Mean valproate concentrations were 96.5 mcg/mL, 102.1 mcg/mL, 98.5
mcg/mL, 89.5 mcg/mL at Days 5, 10, 15 and 21, respectively. Patients were assessed on the
Mania Rating Scale (MRS; score ranges from 0-52).
Depakote ER was significantly more effective than placebo in reduction of the MRS total score.
14.2 Epilepsy
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design, (adjunctive therapy)
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 10. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on
Treatment
Number
of Patients
Baseline
Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for valproate than placebo at
p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for valproate than for placebo. For example, 45% of patients treated with
valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of valproate to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to valproate. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 11. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number
of Patients
Baseline
Incidence
Randomized
Phase Incidence
High dose Valproate
131
13.2
10.7*
Low dose Valproate
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose valproate than for low dose valproate.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
valproate.
Figure 2
Information on pediatric studies are presented in section 8.
14.3 Migraine
The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group
clinical trial demonstrated the effectiveness of Depakote ER in the prophylactic treatment of
migraine headache. This trial recruited patients with a history of migraine headaches with or
without aura occurring on average twice or more a month for the preceding three months.
Patients with cluster or chronic daily headaches were excluded. Women of childbearing potential
were allowed in the trial if they were deemed to be practicing an effective method of
contraception.
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Patients who experienced ≥ 2 migraine headaches in the 4-week baseline period were
randomized in a 1:1 ratio to Depakote ER or placebo and treated for 12 weeks. Patients initiated
treatment on 500 mg once daily for one week, and were then increased to 1000 mg once daily
with an option to permanently decrease the dose back to 500 mg once daily during the second
week of treatment if intolerance occurred. Ninety-eight of 114 Depakote ER-treated patients
(86%) and 100 of 110 placebo-treated patients (91%) treated at least two weeks maintained the
1000 mg once daily dose for the duration of their treatment periods. Treatment outcome was
assessed on the basis of reduction in 4-week migraine headache rate in the treatment period
compared to the baseline period.
Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with Depakote ER
(N=122) or placebo (N=115). Four patients were below the age of 18 and 3 were above the age
of 65. Two hundred and two patients (101 in each treatment group) completed the treatment
period. The mean reduction in 4-week migraine headache rate was 1.2 from a baseline mean of
4.4 in the Depakote ER group, versus 0.6 from a baseline mean of 4.2 in the placebo group. The
treatment difference was statistically significant (see Figure 3).
Figure 3 Mean Reduction In 4-Week Migraine Headache Rates
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
Reference ID: 3520933
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16 HOW SUPPLIED/STORAGE AND HANDLING
Depakote ER 250 mg is available as white ovaloid tablets with the “a” logo and the code (HF).
Each Depakote ER tablet contains divalproex sodium equivalent to 250 mg of valproic acid in
the following package sizes:
Bottles of 60....……………………………………………(NDC 0074-3826-60).
Bottles of 100……………………………………………..(NDC 0074-3826-13).
Bottles of 500……………………………………………..(NDC 0074-3826-53).
Unit Dose Packages of 100..................…………………..(NDC 0074-3826-11).
Depakote ER 500 mg is available as gray ovaloid tablets with the “a” logo and the code HC.
Each Depakote ER tablet contains divalproex sodium equivalent to 500 mg of valproic acid in
the following packaging sizes:
Bottles of 100...................................................................(NDC 0074-7126-13).
Bottles of 500...................................................................(NDC 0074-7126-53).
Unit Dose Packages of 100...............................................(NDC 0074-7126-11).
Recommended Storage
Store tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
Room Temperature].
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
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patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakote ER, may increase
the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-organ Hypersensitivity Reaction
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
17.8 Medication Residue in the Stool
Instruct patients to notify their healthcare provider if they notice a medication residue in the stool
[see Warnings and Precautions (5.18)].
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
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MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old. The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
• If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
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this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
• Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
• Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
• If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
• There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
• Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
• All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
• Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
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o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that do not stop (status
epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
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What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
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What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 950F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering
and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips,
tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A916 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid) capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence
seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
-------DOSAGE FORMS AND STRENGTHS-------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1) Suspected POLG-related disorder in
children under two years of age (4, 5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
• Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
Reference ID: 3520933
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
Reference ID: 3520933
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Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
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5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients
with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at
least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment
discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts
normalized with continued treatment. In this study, the probability of thrombocytopenia
appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or
≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should
therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
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mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
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higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
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Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
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Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
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Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
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Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea,
vomiting, and indigestion. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia
with some weight loss and increased appetite with weight gain have also been reported. The
administration of delayed-release divalproex sodium may result in reduction of gastrointestinal
side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most
often in patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema
multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been
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reported including a fatal case in a 6 month old infant taking valproate and several other
concomitant medications. An additional case of toxic epidermal necrosis resulting in death was
reported in a 35 year old patient with AIDS taking several concomitant medications and with a
history of multiple cutaneous drug reactions. Serious skin reactions have been reported with
concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and
behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis,
and frank hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and
appear to be dose-related. Occasionally, laboratory test results include increases in serum
bilirubin and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.5)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.9)], hyponatremia, and
inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a
cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain,
cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and
hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
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7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
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Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
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Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
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Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
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In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
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Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
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social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
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In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
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The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
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Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote Tablets
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A914 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Depakote safely and effectively. See full prescribing information for
Depakote.
Depakote Sprinkle Capsules (divalproex sodium coated particles in
capsules), for oral use
Initial U.S. Approval: 1989
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 06/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
Warnings and Precautions, Medication Residue in the Stool (5.18) 02/2013
-------INDICATIONS AND USAGE-------
Depakote is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence seizures; adjunctive therapy in patients with
multiple seizure types that include absence seizures (1)
-------DOSAGE AND ADMINISTRATION-------
• Depakote Sprinkle Capsules may be swallowed whole or the contents may
be sprinkled on soft food. The drug/food mixture should be swallowed
immediately (avoid chewing) (2.2)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1
week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response;
if response is not satisfactory, check valproate plasma level; see full
prescribing information for conversion to monotherapy (2.1)
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by
5 to 10 mg/kg/day until seizure control or limiting side effects (2.1)
-------DOSAGE FORMS AND STRENGTHS-------
Capsules: 125 mg (3)
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakote Sprinkle Capsules should ordinarily be
discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakote,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakote Sprinkle
Capsules (5.12)
• Somnolence in the elderly can occur. Depakote Sprinkle Capsules dosage
should be increased slowly and with regular monitoring for fluid and
nutritional intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) are thrombocytopenia,
nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain,
dyspepsia, diarrhea, increased appetite, tremor, weight gain, weight loss,
alopecia, headache, fever, anorexia, constipation, diplopia,
amblyopia/blurred vision, ataxia, nystagmus, emotional lability, thinking
abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis,
ecchymosis, peripheral edema, insomnia, nervousness, depression,
pharyngitis, dyspnea, tinnitus (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakote
Sprinkle Capsules (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakote Sprinkle Capsules can cause congenital
malformations including neural tube defects and decreased IQ (5.2, 5.3,
8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
2.2 General Dosing Advice
1 INDICATIONS AND USAGE
3 DOSAGE FORMS AND STRENGTHS
1.1 Epilepsy
4 CONTRAINDICATIONS
1.2 Important Limitations
5 WARNINGS AND PRECAUTIONS
2 DOSAGE AND ADMINISTRATION
5.1 Hepatotoxicity
2.1 Epilepsy
5.2 Birth Defects
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5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
5.18 Medication Residue in the Stool
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Effect of Disease
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
17.8 Medication Residue in the Stool
17.9 Administration Guide
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate and its derivatives. These incidents usually have occurred during the first six
months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In
patients with epilepsy, a loss of seizure control may also occur. Patients should be
monitored closely for appearance of these symptoms. Serum liver tests should be
performed prior to therapy and at frequent intervals thereafter, especially during the first
six months [see Warnings and Precautions (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakote Sprinkle Capsules are
used in this patient group, they should be used with extreme caution and as a sole agent.
The benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakote Sprinkle Capsules is contraindicated in patients
known to have mitochondrial disorders caused by POLG mutations and children under
two years of age who are clinically suspected of having a mitochondrial disorder [see
Contraindications (4)]. In patients over two years of age who are clinically suspected of
having a hereditary mitochondrial disease, Depakote Sprinkle Capsules should only be
used after other anticonvulsants have failed. This older group of patients should be closely
monitored during treatment with Depakote Sprinkle Capsules for the development of acute
liver injury with regular clinical assessments and serum liver testing. POLG mutation
screening should be performed in accordance with current clinical practice [see Warnings
and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
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valproate use is considered for a condition not usually associated with permanent injury or
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakote Sprinkle Capsules are indicated as monotherapy and adjunctive therapy in the
treatment of adult patients and pediatric patients down to the age of 10 years with complex
partial seizures that occur either in isolation or in association with other types of seizures.
Depakote Sprinkle Capsules are also indicated for use as sole and adjunctive therapy in the
treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakote Sprinkle Capsules are administered orally. As Depakote dosage is titrated upward,
concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital,
carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
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Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote Sprinkle Capsules has not been systematically studied as initial therapy. Patients
should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made.
Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25%
every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1
to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and
duration of withdrawal of the concomitant AED can be highly variable, and patients should be
monitored closely during this period for increased seizure frequency.
Adjunctive Therapy
Depakote Sprinkle Capsules may be added to the patient's regimen at a dosage of 10 to 15
mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical
response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If
satisfactory clinical response has not been achieved, plasma levels should be measured to
determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).
No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can
be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or
phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact
with these or other concurrently administered AEDs as well as other drugs, periodic plasma
concentration determinations of concomitant AEDs are recommended during the early course of
therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
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The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentrations for most patients with
absence seizures are considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakote Sprinkle Capsules dosage is titrated upward, blood concentrations of
phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote Sprinkle
Capsules should be initiated at the same daily dose and dosing schedule. After the patient is
stabilized on Depakote Sprinkle Capsules, a dosing schedule of two or three times a day may be
elected in selected patients.
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
Administration of Sprinkle Capsules
Depakote Sprinkle Capsules may be swallowed whole or may be administered by carefully
opening the capsule and sprinkling the entire contents on a small amount (teaspoonful) of soft
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food such as applesauce or pudding. The drug/food mixture should be swallowed immediately
(avoid chewing) and not stored for future use. Each capsule is oversized to allow ease of
opening.
3 DOSAGE FORMS AND STRENGTHS
Depakote Sprinkle Capsules are for oral administration. Depakote Sprinkle Capsules contain
specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid in a hard
gelatin capsule.
4 CONTRAINDICATIONS
• Depakote Sprinkle Capsules should not be administered to patients with hepatic disease or
significant hepatic dysfunction [see Warnings and Precautions (5.1)].
• Depakote Sprinkle Capsules is contraindicated in patients known to have mitochondrial
disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-
Huttenlocher Syndrome) and children under two years of age who are suspected of having a
POLG-related disorder [see Warnings and Precautions (5.1)].
• Depakote Sprinkle Capsules is contraindicated in patients with known hypersensitivity to the
drug [see Warnings and Precautions (5.12)].
• Depakote Sprinkle Capsules is contraindicated in patients with known urea cycle disorders
[see Warnings and Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
Reference ID: 3520933
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When Depakote is used in this patient group, it should be used with extreme caution and as a
sole agent. The benefits of therapy should be weighed against the risks. In progressively older
patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity
decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakote Sprinkle Capsules is contraindicated in patients known to have mitochondrial disorders
caused by POLG mutations and children under two years of age who are clinically suspected of
having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver
failure and liver-related deaths have been reported in patients with hereditary neurometabolic
syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g.,
Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote Sprinkle Capsules should only be used after other
anticonvulsants have failed. This older group of patients should be closely monitored during
treatment with Depakote Sprinkle Capsules for the development of acute liver injury with regular
clinical assessments and serum liver test monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
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scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]),
carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
Reference ID: 3520933
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several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in
2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be
warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis
that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily
be discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders
Depakote is contraindicated in patients with known urea cycle disorders (UCD).
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakote, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
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The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo
Drug Patients Relative Risk: Incidence of
Risk Difference:
Patients with with Events
Events in Drug
Additional Drug
Events Per
Per 1,000
Patients/Incidence in
Patients with Events
1,000 Patients
Patients
Placebo Patients
Per 1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakote or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy,
34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value
of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with
return of platelet counts to normal. In the remaining patients, platelet counts normalized with
continued treatment. In this study, the probability of thrombocytopenia appeared to increase
significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL
(males). The therapeutic benefit which may accompany the higher doses should therefore be
weighed against the possibility of a greater incidence of adverse effects.
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Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakote be monitored for platelet count and coagulation
parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of
hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured [see Contraindications (4) and Warnings and Precautions
(5.6, 5.10)]. Hyperammonemia should also be considered in patients who present with
hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy
should be discontinued. Appropriate interventions for treatment of hyperammonemia should be
initiated, and such patients should undergo investigation for underlying urea cycle disorders [see
Contraindications (4) and Warnings and Precautions (5.6, 5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not
due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
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organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
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5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown [see Adverse Reactions (6.2)].
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
5.18 Medication Residue in the Stool
There have been rare reports of medication residue in the stool. Some patients have had anatomic
(including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI
transit times. In some reports, medication residues have occurred in the context of diarrhea. It is
recommended that plasma valproate levels be checked in patients who experience medication
residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated,
alternative treatment may be considered.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Hepatic failure (5.1)
Birth defects (5.2)
Decreased IQ following in utero exposure (5.3)
Pancreatitis (5.5)
Hyperammonemic encephalopathy (5.6, 5.9)
Thrombocytopenia (5.8)
Multi-organ hypersensitivity reactions (5.12)
Somnolence in the elderly (5.14)
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
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6.1 Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
In a long term (12-month) safety study in pediatric patients (n=169) between the ages of 3 and 10
years old, no clinically meaningful differences in the adverse event profile were observed when
compared to adults.
Table 2 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in the
placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to
determine whether the following adverse reactions can be ascribed to Depakote alone, or the
combination of Depakote and other antiepilepsy drugs.
Table 2. Adverse Reactions Reported by ≥ 5% of Patients Treated with Valproate During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Event
Depakote (%)
Placebo (%)
(n = 77)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
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Table 2. Adverse Reactions Reported by ≥ 5% of Patients Treated with Valproate During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose valproate group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Valproate Monotherapy for Complex Partial Seizuresa
Body System/Event
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
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Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
a. Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group
and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
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6.2 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal
The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and
indigestion. These effects are usually transient and rarely require discontinuation of therapy.
Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some
weight loss and increased appetite with weight gain have also been reported. The administration
of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in
some patients.
CNS Effects
Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic
Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported
including a fatal case in a 6 month old infant taking valproate and several other concomitant
medications. An additional case of toxic epidermal necrosis resulting in death was reported in a
35 year old patient with AIDS taking several concomitant medications and with a history of
multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant
administration of lamotrigine and valproate [see Drug Interactions (7.2)].
Psychiatric
Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal
Weakness.
Hematologic
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Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected
in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank
hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic
Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to
be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and
abnormal changes in other liver function tests. These results may reflect potentially serious
hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine
Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic
Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].
Metabolic
Hyperammonemia [see Warnings and Precautions (5.9, 5.10)], hyponatremia, and inappropriate
ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in
children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary
Enuresis and urinary tract infection.
Special Senses
Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other
Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia
[see Warnings and Precautions (5.11)].
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
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7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
in not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients
with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronosyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
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Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by
a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance
as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially
along with other anticonvulsants, should be monitored for alterations in serum concentrations of
both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase
in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The
fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
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Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n=11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
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No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9,5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakote, physicians should
encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must
be done by the patients themselves. Information on the registry can be found at the website,
http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
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Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakote Sprinkles should not be used to treat women with epilepsy who are pregnant or
who plan to become pregnant unless other treatments have failed to provide adequate
symptom control or are otherwise unacceptable. In such women, the benefits of treatment
with valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
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There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I.
104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
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social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in
this patient group, it should be used with extreme caution and as a sole agent. The benefits of
therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older
patient groups.
Younger children, especially those receiving enzyme inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults. The variability in free fraction limits the clinical
usefulness of monitoring total serum valproic acid concentration. Interpretation of valproic acid
concentrations in children should include consideration of factors that affect hepatic metabolism
and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were
shown to be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
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In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was
occasionally associated with the latter two events. It is not clear whether these events indicate
additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26) [see Clinical
Pharmacology (12.3)].
8.6 Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), Warnings and Precautions (5), and Clinical
Pharmacology (12.3)]. Liver disease impairs the capacity to eliminate valproate.
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however patients have recovered from valproate levels as high as 2,120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
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11 DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and
valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic
acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen
bis(2-propylpentanoate). Divalproex sodium has the following structure:
Divalproex sodium occurs as a white powder with a characteristic odor.
Depakote Sprinkle Capsules are for oral administration. Depakote Sprinkle Capsules contain
specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid in a hard
gelatin capsule.
Inactive Ingredients
125 mg Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Meets USP Dissolution Test 2.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms
by which valproate exerts its therapeutic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
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12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate may not
provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total
valproate, although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and DEPAKENE (valproic
acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to
8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and DEPAKENE formulations should cause no clinical problems in the management
of patients with epilepsy.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
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valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide)
[see Drug Interactions (7) for more detailed information on the pharmacokinetic interactions of
valproate with other drugs].
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Children
Pediatric patients (i.e., between 3 and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
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There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free
valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute
hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and
larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed
Warning, Contraindications (4), and Warnings and Precautions (5.1)].
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
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Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
14.1 Epilepsy
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy)
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 4. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment Number of Patients
Baseline Incidence
Experimental Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for valproate than placebo at
p ≤ 0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for valproate than for placebo. For example, 45% of patients treated with
valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of valproate to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to valproate. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 5. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of
Baseline Incidence Randomized Phase
Patients
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose valproate than for low dose valproate.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
valproate.
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakote Sprinkle Capsules (divalproex sodium coated particles in capsules), 125 mg, are white
opaque and blue, and are supplied in bottles of 100 (NDC 0074-6114-13) and Unit Dose
Packages of 100 (NDC 0074-6114-11).
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Recommended Storage
Store capsules below 77°F (25°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide.
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakote, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
17.8 Medication Residue in the Stool
Instruct patients to notify their healthcare provider if they notice a medication residue in the stool
[see Warnings and Precautions (5.18)].
17.9 Administration Guide
DEPAKOTE®
Sprinkle Capsules
DIVALPROEX SODIUM
COATED PARTICLES IN CAPSULES
DEPAKOTE® Sprinkle Capsules (divalproex sodium coated particles in capsules) may be
swallowed whole or the capsule contents may be sprinkled onto soft food such as applesauce or
pudding.
Serving Suggestions
Depakote ® Sprinkle Capsules (divalproex sodium coated particles in capsules) provide the
medicine that your healthcare provider has prescribed. The sprinkles are flavorless. Soft foods
such as applesauce or pudding are best to use for mixing and taking Depakote Sprinkles.
TO ADMINISTER WITH FOOD:
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
us
ag
e
il
lu
st
ra
tion
Hold the capsule so that the end marked "THIS END UP" is straight up and the
arrow on the capsule is up. The capsule is extra large to help prevent spilling
the DEPAKOTE Sprinkles, but it still must be handled carefully.
To open the capsule, hold it carefully. As shown in the picture, gently twist the
capsule apart to separate the top from the bottom. It may be helpful to hold the
capsule over the food to which you will add the sprinkles. If you spill any of
the capsule contents, start over with a new capsule and a new portion of food.
Place all the sprinkles onto a small amount (about a teaspoonful) of soft food
such as applesauce or pudding.
Make sure that all of the sprinkle and food mixture is swallowed right away.
Do not chew the sprinkle and food mixture. Drinking water right after taking
the sprinkle and food mixture will help make sure all sprinkles are swallowed.
Throw away any unused sprinkle and food mixture; do not store any sprinkle
and food mixture for future use. Mix it each time, right before it is taken.
Make sure this medicine is taken exactly as your healthcare provider prescribed it. If you have
any questions, please contact your healthcare provider or pharmacist. Keep all of your healthcare
provider's appointments as scheduled. Make sure that Depakote Sprinkle Capsules and all other
medicines are kept out of the reach of children.
Note
You may see the specially coated particles in Depakote Sprinkle Capsules in stool. If you do, you
should inform your healthcare provider.
Ask your healthcare provider or pharmacist about possible side effects with Depakote Sprinkle
Capsules.
Store Depakote Sprinkle Capsules below 77°F (25°C).
AbbVie Inc.
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking a Depakote or Depakene and each time you
get a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote or Depakene?
Do not stop Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old. The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of childbearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
o severe stomach pain that you may also feel in your back
o nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
Reference ID: 3520933
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o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status
epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder
• alone or with other medicines to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Administration Guide at the end of this Medication Guide for detailed instructions on
how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affects you. Depakote and Depakene can slow your thinking and motor skills.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects with Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene can cause serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering
and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips,
tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules between 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A915 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEPAKENE safely and effectively. See full prescribing information for
DEPAKENE.
DEPAKENE (valproic acid) capsules and oral solution, USP
Initial U.S. Approval: 1978
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depakene is an anti-epileptic drug indicated for:
• Monotherapy and adjunctive therapy of complex partial seizures; sole and
adjunctive therapy of simple and complex absence seizures; adjunctive
therapy in patients with multiple seizure types that include absence
seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depakene is intended for oral administration. (2.1)
• Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day,
increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control
or limiting side effects (2.1)
• Safety of doses above 60 mg/kg/day is not established (2.1, 2.2)
-------DOSAGE FORMS AND STRENGTHS-------
Capsules: 250 mg valproic acid
Syrup: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1) Suspected POLG-related disorder in
children under two years of age (4, 5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakene should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakene,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakene (5.12)
• Somnolence in the elderly can occur. Depakene dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) are abdominal pain,
alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia,
bronchitis, constipation, depression, diarrhea, diplopia, dizziness,
dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome,
headache, increased appetite, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss. (6.1)
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakene (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakene can cause congenital malformations including
neural tube defects and decreased IQ (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1 INDICATIONS AND USAGE
1.1 Epilepsy
1.2 Important Limitations
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
2.2 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
Reference ID: 3520933
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders (UCD)
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
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5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate. These incidents usually have occurred during the first six months of treatment.
Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise,
weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss
of seizure control may also occur. Patients should be monitored closely for appearance of
these symptoms. Serum liver tests should be performed prior to therapy and at frequent
intervals thereafter, especially during the first six months [see Warnings and Precautions
(5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakene products are used in
this patient group, they should be used with extreme caution and as a sole agent. The
benefits of therapy should be weighed against the risks. The incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakene for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
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death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of
patients with complex partial seizures that occur either in isolation or in association with other
types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in
the treatment of simple and complex absence seizures, and adjunctively in patients with multiple
seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depakene is intended for oral administration. Depakene capsules should be swallowed whole
without chewing to avoid local irritation of the mouth and throat.
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Patients should be informed to take Depakene every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
Depakene is indicated as monotherapy and adjunctive therapy in complex partial seizures in
adults and pediatric patients down to the age of 10 years, and in simple and complex absence
seizures. As the Depakene dosage is titrated upward, concentrations of clonazepam, diazepam,
ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be
affected [see Drug Interactions (7.2)].
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakene has not been systematically studied as initial therapy. Patients should initiate therapy
at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakene therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakene may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
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regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to Depakote tablets, no adjustment of
carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since
valproate may interact with these or other concurrently administered AEDs as well as other
drugs, periodic plasma concentration determinations of concomitant AEDs are recommended
during the early course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakene dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
The following Table is a guide for the initial daily dose of Depakene (valproic acid) (15
mg/kg/day):
Table 1. Initial Daily Dose
Weight
Total Daily Dose (mg)
Number of Capsules or
Teaspoonfuls of Syrup
(Kg)
(Lb)
Dose 1
Dose 2
Dose 3
10 - 24.9
22 - 54.9
250
0
0
1
25 - 39.9
55 - 87.9
500
1
0
1
40 - 59.9
88 - 131.9
750
1
1
1
60 - 74.9
132 - 164.9
1,000
1
1
2
75 - 89.9
165 - 197.9
1,250
2
1
2
2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
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dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules and as
a red Oral Solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium
salt in bottles of 16 ounces.
4 CONTRAINDICATIONS
• Depakene should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakene is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakene is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
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anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakene products are used in this patient group, they should be used with extreme
caution and as a sole agent. The benefits of therapy should be weighed against the risks. In
progressively older patient groups experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakene should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakene for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
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5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105-110]),
carbamazepine (105 [95% C.I. 102-108]), and phenytoin (108 [95% C.I. 104-112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
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To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders (UCD)
Valproic acid is contraindicated in patients with known urea cycle disorders.
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakene, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
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Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients
with Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence
of Events in Drug
Patients/Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with Events Per
1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakene or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
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or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of Depakote (divalproex sodium) as monotherapy in patients
with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at
least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment
discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts
normalized with continued treatment. In this study, the probability of thrombocytopenia
appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or
≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should
therefore be weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakene (valproic acid) be monitored for platelet count
and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a
disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of
therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
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mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
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higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Epilepsy
The data described in the following section were obtained using Depakote (divalproex sodium)
tablets.
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
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Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in a placebo-
controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients
were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine
whether the following adverse reactions can be ascribed to Depakote alone, or the combination
of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
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Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose Depakote group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Depakote Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
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Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with Depakote in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depakene has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
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Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital System: Dysuria.
6.3 Migraine
Although Depakene has not been evaluated for safety and efficacy in the treatment of
prophylaxis of migraine headaches, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea,
vomiting, and indigestion. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia
with some weight loss and increased appetite with weight gain have also been reported. The
administration of delayed-release divalproex sodium may result in reduction of gastrointestinal
side effects in some patients.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most
often in patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema
multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been
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reported including a fatal case in a 6 month old infant taking valproate and several other
concomitant medications. An additional case of toxic epidermal necrosis resulting in death was
reported in a 35 year old patient with AIDS taking several concomitant medications and with a
history of multiple cutaneous drug reactions. Serious skin reactions have been reported with
concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and
behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis,
and frank hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and
appear to be dose-related. Occasionally, laboratory test results include increases in serum
bilirubin and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic: Acute pancreatitis, including fatalities [see Warnings and Precautions (5.5)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.9)], hyponatremia, and
inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a
cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain,
cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and
hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
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7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
is not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
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Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
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Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
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Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakene, physicians should
encourage pregnant patients taking Depakene to enroll in the NAAED Pregnancy Registry. This
can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves.
Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
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In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Depakene should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
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Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% – 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 – 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105-110]), carbamazepine (105 [95% C.I. 102-108]) and phenytoin (108 [95% C.I.
104-112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
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social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning]. When Depakene is used in this patient group, it should be used
with extreme caution and as a sole agent. The benefits of therapy should be weighed against the
risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal
hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproic acid concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven trials, the safety and tolerability of Depakote in pediatric patients were shown to
be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
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In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated with the latter two events. It is not clear
whether these events indicate additional risk or whether they result from preexisting medical
illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however, patients have recovered from valproate levels as high as 2120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depakene (valproic acid) is a carboxylic acid designated as 2-propylpentanoic acid. It is also
known as dipropylacetic acid. Valproic acid has the following structure:
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Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a
characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic
solvents.
Depakene capsules and syrup are antiepileptics for oral administration. Each soft elastic capsule
contains 250 mg valproic acid. The syrup contains the equivalent of 250 mg valproic acid per 5
mL as the sodium salt.
Inactive Ingredients
250 mg capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide, methylparaben,
propylparaben, and titanium dioxide.
Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben, sorbitol, sucrose,
water, and natural and artificial flavors.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by
which valproate exerts its antiepileptic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
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The therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate,
although some patients may be controlled with lower or higher plasma concentrations.
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the Depakote tablet (increase in Tmax
from 4 to 8 hours) than on the absorption of the Depakote sprinkle capsules (increase in Tmax
from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.1)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and
tolbutamide). (See Drug Interactions (7.2) for more detailed information on the pharmacokinetic
interactions of valproate with other drugs.)
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
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Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
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There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
[See Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]. Liver disease
impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was
decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,
compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12
to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger
unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal.
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
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Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted using Depakote (divalproex
sodium) tablets.
14.1 Epilepsy
The efficacy of Depakote in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 5. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for Depakote than placebo at p ≤
0.05 level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for Depakote than for placebo. For example, 45% of patients treated with
Depakote had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of Depakote to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to Depakote. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 6. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Reference ID: 3520933
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose Depakote than for low dose Depakote.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose Depakote monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
Depakote.
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakene (valproic acid) is available as orange-colored soft gelatin capsules of 250 mg valproic
acid, bearing the trademark Depakene for product identification, in bottles of 100 capsules (NDC
Reference ID: 3520933
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0074-5681-13), and as a red Oral Solution containing the equivalent of 250 mg valproic acid per
5 mL as the sodium salt in bottles of 16 ounces (NDC 0074-5682-16).
Store capsules at 59-77°F (15-25°C). Store Oral Solution below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of
antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233
2334 [see Use in Specific Populations (8.1)].
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakene, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
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17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote and Depakene?
Do not stop taking Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of child-bearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider. Stopping
Depakote or Depakene suddenly can cause serious problems. Stopping a seizure medicine
suddenly in a patient who has epilepsy can cause seizures that do not stop (status epilepticus).
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal
thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder.
• alone or with other medicines to treat:
o complex partial seizures in adults and children 10 years of age and older
o simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Patient Instructions for Use at the end of this Medication Guide for detailed
instructions on how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affect you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects of Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Depakote or Depakene may cause other serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, skin
blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face,
eyes, lips, tongue, or throat, trouble swallowing or breathing.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
• Store Depakene Capsules at 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote:
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote Tablets
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral solution
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A914 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Depakote safely and effectively. See full prescribing information for
Depakote.
Depakote (divalproex sodium) Tablets for Oral use
Initial U.S. Approval: 1983
WARNINGS: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.
• Hepatotoxicity, including fatalities, usually during the first 6 months
of treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 05/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Contraindications, Prophylaxis of Migraines in Pregnancy (4) 06/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
Warnings and Precautions, Medication Residue in the Stool (5.18) 02/2013
-------INDICATIONS AND USAGE-------
Depakote is an anti-epileptic drug indicated for:
• Treatment of manic episodes associated with bipolar disorder (1.1)
• Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence seizures; adjunctive therapy in patients with
multiple seizure types that include absence seizures (1.2)
• Prophylaxis of migraine headaches (1.3)
-------DOSAGE AND ADMINISTRATION-------
• Depakote is administered orally in divided doses. Depakote should be
swallowed whole and should not be crushed or chewed (2.1, 2.2).
• Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to
achieve therapeutic response or desired plasma level (2.1). The maximum
recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1
week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response;
if response is not satisfactory, check valproate plasma level; see full
prescribing information for conversion to monotherapy (2.2). The
maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by
5 to 10 mg/kg/day until seizure control or limiting side effects (2.2). The
maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).
• Migraine: The recommended starting dose is 250 mg twice daily,
thereafter increasing to a maximum of 1000 mg/day as needed (2.3).
-------DOSAGE FORMS AND STRENGTHS-------
Tablets: 125 mg, 250 mg and 500 mg (3)
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.12)
• Urea cycle disorders (4, 5.6)
• Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy or bipolar disorder if other
medications are unacceptable; should not be administered to a woman of
childbearing potential unless essential (5.2, 5.3, 5.4)
• Pancreatitis; Depakote should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including Depakote,
increase the risk of suicidal thoughts or behavior (5.7)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status, and also with concomitant topiramate use; consider discontinuation
of valproate therapy (5.6, 5.9, 5.10)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.11)
• Multi-organ hypersensitivity reaction; discontinue Depakote (5.12)
• Somnolence in the elderly can occur. Depakote dosage should be
increased slowly and with regular monitoring for fluid and nutritional
intake (5.14)
-------ADVERSE REACTIONS-------
• Most common adverse reactions (reported >5%) reported in patients are
abdominal pain, accidental injury, alopecia, ambylopia/blurred vision,
amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation,
depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis,
emotional lability, fever, flu syndrome, headache, increased appetite,
infection, insomnia, nausea, nervousness, nystagmus, peripheral edema,
pharyngitis, rash, rhinitis, somnolence, thinking abnormal,
thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss
(6.1, 6.2, 6.3).
• The safety and tolerability of valproate in pediatric patients were shown to
be comparable to those in adults (8.4).
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
primidone, phenobarbital, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dose adjustment is indicated whenever enzyme-
inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations
are recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depakote (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depakote can cause congenital malformations including neural
tube defects and decreased IQ. (5.2, 5.3, 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose; increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.14, 8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
1.3 Migraine
1 INDICATIONS AND USAGE
1.4 Important Limitations
1.1 Mania
2 DOSAGE AND ADMINISTRATION
1.2 Epilepsy
2.1 Mania
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2 Epilepsy
2.3 Migraine
2.4 General Dosing Advice
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 Birth Defects
5.3 Decreased IQ Following in utero Exposure
5.4 Use in Women of Childbearing Potential
5.5 Pancreatitis
5.6 Urea Cycle Disorders
5.7 Suicidal Behavior and Ideation
5.8 Thrombocytopenia
5.9 Hyperammonemia
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant
Topiramate Use
5.11 Hypothermia
5.12 Multi-Organ Hypersensitivity Reactions
5.13 Interaction with Carbapenem Antibiotics
5.14 Somnolence in the Elderly
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
5.18 Medication Residue in the Stool
6 ADVERSE REACTIONS
6.1 Mania
6.2 Epilepsy
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Mania
14.2 Epilepsy
14.3 Migraine
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Suicidal Thinking and Behavior
17.5 Hyperammonemia
17.6 CNS Depression
17.7 Multi-Organ Hypersensitivity Reactions
17.8 Medication Residue in the Stool
MEDICATION GUIDE
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate and its derivatives. These incidents usually have occurred during the first six
months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In
patients with epilepsy, a loss of seizure control may also occur. Patients should be
monitored closely for appearance of these symptoms. Serum liver tests should be
performed prior to therapy and at frequent intervals thereafter, especially during the first
six months [see Warnings and Precautions (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depakote is used in this patient
group, it should be used with extreme caution and as a sole agent. The benefits of therapy
should be weighed against the risks. The incidence of fatal hepatotoxicity decreases
considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depakote is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depakote for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate is therefore contraindicated in pregnant women treated for prophylaxis of
migraine [see Contraindications (4)]. Valproate should only be used to treat pregnant
women with epilepsy or bipolar disorder if other medications have failed to control their
symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4)].
A Medication Guide describing the risks of valproate is available for patients [see Patient
Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Mania
Depakote (divalproex sodium) is a valproate and is indicated for the treatment of the manic
episodes associated with bipolar disorder. A manic episode is a distinct period of abnormally and
persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure
of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor
judgment, aggressiveness, and possible hostility.
The efficacy of Depakote was established in 3-week trials with patients meeting DSM-III-R
criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1)].
The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks,
has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect
to use Depakote for extended periods should continually reevaluate the long-term usefulness of
the drug for the individual patient.
1.2 Epilepsy
Depakote is indicated as monotherapy and adjunctive therapy in the treatment of patients with
complex partial seizures that occur either in isolation or in association with other types of
seizures. Depakote is also indicated for use as sole and adjunctive therapy in the treatment of
simple and complex absence seizures, and adjunctively in patients with multiple seizure types
that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
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1.3 Migraine
Depakote is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote
is useful in the acute treatment of migraine headaches.
1.4 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant.
2 DOSAGE AND ADMINISTRATION
Depakote tablets are intended for oral administration. Depakote tablets should be swallowed
whole and should not be crushed or chewed.
Patients should be informed to take Depakote every day as prescribed. If a dose is missed it
should be taken as soon as possible, unless it is almost time for the next dose. If a dose is
skipped, the patient should not double the next dose.
2.1 Mania
Depakote tablets are administered orally. The recommended initial dose is 750 mg daily in
divided doses. The dose should be increased as rapidly as possible to achieve the lowest
therapeutic dose which produces the desired clinical effect or the desired range of plasma
concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a
clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum
concentrations were generally achieved within 14 days. The maximum recommended dosage is
60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer
term management of a patient who improves during Depakote treatment of an acute manic
episode. While it is generally agreed that pharmacological treatment beyond an acute response in
mania is desirable, both for maintenance of the initial response and for prevention of new manic
episodes, there are no data to support the benefits of Depakote in such longer-term treatment.
Although there are no efficacy data that specifically address longer-term antimanic treatment
with Depakote, the safety of Depakote in long-term use is supported by data from record reviews
involving approximately 360 patients treated with Depakote for greater than 3 months.
2.2 Epilepsy
Depakote tablets are administered orally. Depakote is indicated as monotherapy and adjunctive
therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years,
and in simple and complex absence seizures. As the Depakote dosage is titrated upward,
concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital,
carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].
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Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at
10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal
clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or
phenytoin dosage was needed [see Clinical Studies (14.2)]. However, since valproate may
interact with these or other concurrently administered AEDs as well as other drugs, periodic
plasma concentration determinations of concomitant AEDs are recommended during the early
course of therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
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The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentrations for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets
should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on
Depakote tablets, a dosing schedule of two or three times a day may be elected in selected
patients.
2.3 Migraine
Depakote is indicated for prophylaxis of migraine headaches in adults.
Depakote tablets are administered orally. The recommended starting dose is 250 mg twice daily.
Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no
evidence that higher doses led to greater efficacy.
2.4 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.14), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.8)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
G.I. Irritation
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Patients who experience G.I. irritation may benefit from administration of the drug with food or
by slowly building up the dose from an initial low level.
3 DOSAGE FORMS AND STRENGTHS
Depakote tablets (divalproex sodium delayed-release tablets) are supplied as:
125 mg salmon pink-colored tablets
250 mg peach-colored tablets
500 mg lavender-colored tablets
4 CONTRAINDICATIONS
• Depakote should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depakote is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depakote is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.12)].
• Depakote is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
• Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women
[see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months. However, healthcare providers should not rely totally on serum biochemistry since these
tests may not be abnormal in all instances, but should also consider the results of careful interim
medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
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those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depakote is used in this patient group, it should be used with extreme caution and as a
sole agent. The benefits of therapy should be weighed against the risks. In progressively older
patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity
decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depakote should only be used after other anticonvulsants have failed.
This older group of patients should be closely monitored during treatment with Depakote for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
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5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]),
carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of
migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to
become pregnant should not be treated with valproate unless other treatments have failed to
provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
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5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in
2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be
warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis
that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily
be discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
5.6 Urea Cycle Disorders
Depakote is contraindicated in patients with known urea cycle disorders (UCD).
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.10)].
5.7 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Depakote, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of depression, suicidal thoughts
or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median treatment duration of 12
weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated
patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an
increase of approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
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The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one
week after starting drug treatment with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk
of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk
did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1. Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo
Patients with
Events Per
1,000 Patients
Drug Patients
with Events
Per 1,000
Patients
Relative Risk: Incidence of
Events in Drug
Patients/Incidence in
Placebo Patients
Risk Difference:
Additional Drug
Patients with Events
Per 1,000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for
the epilepsy and psychiatric indications.
Anyone considering prescribing Depakote or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for
which AEDs are prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge
during treatment, the prescriber needs to consider whether the emergence of these symptoms in
any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of
concern should be reported immediately to healthcare providers.
5.8 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126
patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of
platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with
return of platelet counts to normal. In the remaining patients, platelet counts normalized with
continued treatment. In this study, the probability of thrombocytopenia appeared to increase
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significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL
(males). The therapeutic benefit which may accompany the higher doses should therefore be
weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depakote be monitored for platelet count and coagulation
parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of
hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
5.9 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.11)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.10)].
Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.6, 5.9)].
5.11 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
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topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.12 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.13 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.14 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.4)].
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5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
5.18 Medication Residue in the Stool
There have been rare reports of medication residue in the stool. Some patients have had anatomic
(including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI
transit times. In some reports, medication residues have occurred in the context of diarrhea. It is
recommended that plasma valproate levels be checked in patients who experience medication
residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated,
alternative treatment may be considered.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
6.1 Mania
The incidence of treatment-emergent events has been ascertained based on combined data from
two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes
associated with bipolar disorder. The adverse reactions were usually mild or moderate in
intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of
premature termination due to intolerance were not statistically different between placebo,
Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy
due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively.
Table 2 summarizes those adverse reactions reported for patients in these trials where the
incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo
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incidence, or where the incidence in the Depakote-treated group was statistically significantly
greater than the placebo group. Vomiting was the only reaction that was reported by significantly
(p ≤ 0.05) more patients receiving Depakote compared to placebo.
Table 2. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During
Placebo-Controlled Trials of Acute Mania1
Adverse Reaction
Depakote
(n = 89)
Placebo
(n = 97)
Nausea
22%
15%
Somnolence
19%
12%
Dizziness
12%
4%
Vomiting
12%
3%
Accidental Injury
11%
5%
Asthenia
10%
7%
Abdominal pain
9%
8%
Dyspepsia
9%
8%
Rash
6%
3%
1. The following adverse reactions occurred at an equal or greater incidence for placebo than
for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.
The following additional adverse reactions were reported by greater than 1% but not more than
5% of the 89 Depakote-treated patients in controlled clinical trials:
Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.
Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension,
tachycardia, vasodilation.
Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal
abscess.
Hemic and Lymphatic System: Ecchymosis.
Metabolic and Nutritional Disorders: Edema, peripheral edema.
Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.
Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction,
confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia,
paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.
Respiratory System: Dyspnea, rhinitis.
Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis,
maculopapular rash, seborrhea.
Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.
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Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.
6.2 Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to
moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote
treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in the
placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to
determine whether the following adverse reactions can be ascribed to Depakote alone, or the
combination of Depakote and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
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Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
Alopecia
6
1
Weight Loss
6
0
Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose valproate group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
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Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1. Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.3 Migraine
Based on two placebo-controlled clinical trials and their long term extension, valproate was
generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the
202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for
intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term
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extension study, the adverse reactions reported as the primary reason for discontinuation by ≥
1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight
gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression
(1%).
Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials
where the incidence rate in the Depakote-treated group was greater than 5% and was greater than
that for placebo patients.
Table 5. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During
Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking
Placebo1
Body System Reaction
Depakote
(N = 202)
Placebo
(N = 81)
Gastrointestinal System
Nausea
31%
10%
Dyspepsia
13%
9%
Diarrhea
12%
7%
Vomiting
11%
1%
Abdominal pain
9%
4%
Increased appetite
6%
4%
Nervous System
Asthenia
20%
9%
Somnolence
17%
5%
Dizziness
12%
6%
Tremor
9%
0%
Other
Weight gain
8%
2%
Back pain
8%
6%
Alopecia
7%
1%
1. The following adverse reactions occurred in at least 5% of Depakote-treated patients and at
an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis.
The following additional adverse reactions were reported by greater than 1% but not more than
5% of the 202 Depakote-treated patients in the controlled clinical trials:
Body as a Whole: Chest pain, chills, face edema, fever and malaise.
Cardiovascular System: Vasodilatation.
Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder
(unspecified), and stomatitis.
Hemic and Lymphatic System: Ecchymosis.
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Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.
Musculoskeletal System: Leg cramps and myalgia.
Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability,
insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.
Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.
Skin and Appendages: Pruritus and rash.
Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal
The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and
indigestion. These effects are usually transient and rarely require discontinuation of therapy.
Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some
weight loss and increased appetite with weight gain have also been reported. The administration
of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in
some patients.
CNS Effects
Sedative effects have occurred in patients receiving valproate alone but occur most often in
patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic
Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and
Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported
including a fatal case in a 6 month old infant taking valproate and several other concomitant
medications. An additional case of toxic epidermal necrosis resulting in death was reported in a
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35 year old patient with AIDS taking several concomitant medications and with a history of
multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant
administration of lamotrigine and valproate [see Drug Interactions (7.2)].
Psychiatric
Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral
deterioration.
Musculoskeletal
Weakness.
Hematologic
Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected
in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank
hemorrhage [see Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic
Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to
be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and
abnormal changes in other liver function tests. These results may reflect potentially serious
hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine
Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland
swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic
Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].
Metabolic
Hyperammonemia [see Warnings and Precautions (5.9, 5.10)], hyponatremia, and inappropriate
ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary
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Enuresis and urinary tract infection.
Special Senses
Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect
relationship has not been established. Ear pain has also been reported.
Other
Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough
increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia
[see Warnings and Precautions (5.11)].
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
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A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this
is not a complete list) and may result in loss of seizure control. The mechanism of this interaction
in not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.13)].
Felbamate
A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients
with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronosyltransferases.
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The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by
a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance
as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially
along with other anticonvulsants, should be monitored for alterations in serum concentrations of
both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
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Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase
in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The
fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
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Clozapine
In psychotic patients (n=11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.6, 5.9, 5.10)]. Concomitant administration of topiramate with valproate has
also been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.9, 5.11)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder
[see Warnings and Precautions (5.2, 5.3)].
Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depakote, physicians should
encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must
be done by the patients themselves. Information on the registry can be found at the website,
http://www.aedpregnancyregistry.org/.
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Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Valproate is contraindicated during pregnancy in women being treated for prophylaxis of
migraine headaches.
• Valproate should not be used to treat women with epilepsy or bipolar disorder who are
pregnant or who plan to become pregnant unless other treatments have failed to provide
adequate symptom control or are otherwise unacceptable. In such women, the benefits of
treatment with valproate during pregnancy may still outweigh the risks. When treating a
pregnant woman or a woman of childbearing potential, carefully consider both the
potential risks and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
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• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.8)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I.
104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
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Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience has indicated that pediatric patients under the age of two years are at a considerably
increased risk of developing fatal hepatotoxicity, especially those with the aforementioned
conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in
this patient group, it should be used with extreme caution and as a sole agent. The benefits of
therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has
indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older
patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric
patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight
(i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic
parameters that approximate those of adults.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
Depakote was studied in seven pediatric clinical trials.
Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the
efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of
whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were
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on Depakote ER). Efficacy was not established for either the treatment of migraine or the
treatment of mania. The most common drug-related adverse reactions (reported >5% and twice
the rate of placebo) reported in the controlled pediatric mania study were nausea, upper
abdominal pain, somnolence, increased ammonia, gastritis and rash.
The remaining five trials were long term safety studies. Two six-month pediatric studies were
conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292
patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate
the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17
years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle
Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).
In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were
shown to be comparable to those in adults [see Adverse Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was
occasionally associated with the latter two events. It is not clear whether these events indicate
additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.4)].
There is insufficient information available to discern the safety and effectiveness of valproate for
the prophylaxis of migraines in patients over 65.
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however patients have recovered from valproate levels as high as 2,120
mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit
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of gastric lavage or emesis will vary with the time since ingestion. General supportive measures
should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and
valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic
acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen
bis(2-propylpentanoate). Divalproex sodium has the following structure:
Divalproex sodium occurs as a white powder with a characteristic odor.
Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage
strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic
acid.
Inactive Ingredients
Depakote tablets: cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized
starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
In addition, individual tablets contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40.
250 mg tablets: FD&C Yellow No. 6 and iron oxide.
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms
by which valproate exerts its therapeutic effects have not been established. It has been suggested
that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric
acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total
valproate, although some patients may be controlled with lower or higher plasma concentrations.
Mania
In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with
trough plasma concentrations between 50 and 125 mcg/mL [see Dosage and Administration
(2.1)].
12.3 Pharmacokinetics
Absorption/Bioavailability
Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid)
capsules deliver equivalent quantities of valproate ion systemically. Although the rate of
valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle),
conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether
the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences
should be of minor clinical importance under the steady state conditions achieved in chronic use
in the treatment of epilepsy.
However, it is possible that differences among the various valproate products in Tmax and Cmax
could be important upon initiation of treatment. For example, in single dose studies, the effect of
feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to
8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations
vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in
chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to
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four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion,
indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant
of seizure control and that differences in the ratios of plasma peak to trough concentrations
between valproate formulations are inconsequential from a practical clinical standpoint. Whether
or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine
agent is unknown.
Co-administration of oral valproate products with food and substitution among the various
Depakote and Depakene formulations should cause no clinical problems in the management of
patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in
dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily
be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide)
[see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions
of valproate with other drugs].
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate
are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged
from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
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these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.4)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free
valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute
hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and
larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed
Warning, Contraindications (4) and Warnings and Precautions (5.1)].
Renal Disease
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A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60
days. The effect of valproate on testicular development and on sperm production and fertility in
humans is unknown.
14 CLINICAL STUDIES
14.1 Mania
The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week,
placebo controlled, parallel group studies.
(1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar
disorder and who were hospitalized for acute mania. In addition, they had a history of failing to
respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a
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dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100
mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and
2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania
Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale
(BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline
in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows:
Table 6. Study 1
YMRS Total Score
Group
Baseline1
BL to Wk 32
Difference3
Placebo
28.8
+ 0.2
Depakote
28.5
- 9.5
9.7
BPRS-A Total Score
Group
Baseline1
BL to Wk 32
Difference3
Placebo
76.2
+ 1.8
Depakote
76.4
-17.0
18.8
GAS Score
Group
Baseline1
BL to Wk 32
Difference3
Placebo
31.8
0.0
Depakote
30.3
+ 18.1
18.1
1. Mean score at baseline
2. Change from baseline to Week 3 (LOCF)
3. Difference in change from baseline to Week 3 endpoint (LOCF) between Depakote and
placebo
Depakote was statistically significantly superior to placebo on all three measures of outcome.
(2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for
manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of
250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate
concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study
were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a
lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at
Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score
ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for
two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation
Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation
carry-forward) analysis were as follows:
Table 7. Study 2
MRS Total Score
Group
Baseline1
BL to Day 212
Difference3
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Placebo
38.9
- 4.4
Lithium
37.9
-10.5
6.1
Depakote
38.1
- 9.5
5.1
MSS Total Score
Group
Baseline1
BL to Day 212
Difference3
Placebo
18.9
- 2.5
Lithium
18.5
- 6.2
3.7
Depakote
18.9
- 6.0
3.5
BIS Total Score
Group
Baseline1
BL to Day 212
Difference3
Placebo
16.4
- 1.4
Lithium
16.0
- 3.8
2.4
Depakote
15.7
- 3.2
1.8
1. Mean score at baseline
2. Change from baseline to Day 21 (LOCF)
3. Difference in change from baseline to Day 21 endpoint (LOCF) between Depakote and
placebo and lithium and placebo
Depakote was statistically significantly superior to placebo on all three measures of outcome. An
exploratory analysis for age and gender effects on outcome did not suggest any differential
responsiveness on the basis of age or gender.
A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from
baseline in each treatment group, separated by study, is shown in Figure 1.
Figure 1
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* p < 0.05
PBO = placebo, DVPX = Depakote
14.2 Epilepsy
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy)
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 8. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on
Treatment
Number
of Patients
Baseline
Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for valproate than placebo at p ≤
0.05 level.
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Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for valproate than for placebo. For example, 45% of patients treated with
valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 2
The second study assessed the capacity of valproate to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to valproate. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 9. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of
Patients
Baseline
Incidence
Randomized
Phase Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose valproate than for low dose valproate.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
valproate.
Figure 3
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14.3 Migraine
The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials
established the effectiveness of Depakote in the prophylactic treatment of migraine headache.
Both studies employed essentially identical designs and recruited patients with a history of
migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2
migraine headaches a month during the 3 months prior to enrollment. Patients with cluster
headaches were excluded. Women of childbearing potential were excluded entirely from one
study, but were permitted in the other if they were deemed to be practicing an effective method
of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were
randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment
phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period.
Treatment outcome was assessed on the basis of 4-week migraine headache rates during the
treatment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were
randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period.
Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion.
Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain
the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over
500 mg were given in three divided doses (TID). The mean dose during the treatment phase was
1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31
to 133 mcg/mL.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo
group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly
different.
In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to
76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500
mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-
seven patients completed the 8-week maintenance period. Efficacy was to be determined by a
comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group
and placebo group.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days
for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate
levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000,
and 1,500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in
baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500,
1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4).
Migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly
lower than in the placebo group.
Figure 4 Mean 4-week Migraine Rates
Reference ID: 3520933
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1 Mean dose of Depakote was 1,087 mg/day.
2 Dose of Depakote was 500 or 1,000 mg/day.
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depakote tablets (divalproex sodium delayed-release tablets) are supplied as:
125 mg salmon pink-colored tablets:
Bottles of 100………………………………………..(NDC 0074-6212-13)
Unit Dose Packages of 100.................………………(NDC 0074-6212-11)
250 mg peach-colored tablets:
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Bottles of 100……………………………………….(NDC 0074-6214-13)
Bottles of 500……………………………………….(NDC 0074-6214-53)
Unit Dose Packages of 100................………………(NDC 0074-6214-11)
500 mg lavender-colored tablets:
Bottles of 100……………………………………….(NDC 0074-6215-13)
Bottles of 500……………………………………….(NDC 0074-6215-53)
Unit Dose Packages of 100................……………...(NDC 0074-6215-11)
Recommended storage
Store tablets below 86°F (30°C).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Medication Guide.
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death. Advise
patients to read the Medication Guide, which appears as the last section of the labeling [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations
(8.1)].
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.4 Suicidal Thinking and Behavior
Counsel patients, their caregivers, and families that AEDs, including Depakote, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients,
caregivers, and families to report behaviors of concern immediately to the healthcare providers
[see Warnings and Precautions (5.7)].
17.5 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.9, 5.10)].
17.6 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.7 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.12)].
17.8 Medication Residue in the Stool
Instruct patients to notify their healthcare provider if they notice a medication residue in the stool
[see Warnings and Precautions (5.18)].
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
MEDICATION GUIDE
DEPAKOTE ER (dep-a-kOte)
(divalproex sodium)
Extended Release Tablets
DEPAKOTE (dep-a-kOte)
(divalproex sodium)
Tablets
DEPAKOTE (dep-a-kOte)
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(divalproex sodium)
Sprinkle Capsules
DEPAKENE (dep-a-keen)
(valproic acid)
Capsules and Oral Solution
Read this Medication Guide before you start taking Depakote or Depakene and each time you get
a refill. There may be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
What is the most important information I should know about Depakote or Depakene?
Do not stop Depakote or Depakene without first talking to your healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems.
Depakote and Depakene can cause serious side effects, including:
1. Serious liver damage that can cause death, especially in children younger than 2 years
old.
The risk of getting this serious liver damage is more likely to happen within the first 6
months of treatment.
Call your healthcare provider right away if you get any of the following symptoms:
o nausea or vomiting that does not go away
o loss of appetite
o pain on the right side of your stomach (abdomen)
o dark urine
o swelling of your face
o yellowing of your skin or the whites of your eyes
In some cases, liver damage may continue despite stopping the drug.
2. Depakote or Depakene may harm your unborn baby.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
baby is at risk for serious birth defects. The most common birth defects with Depakote or
Depakene affect the brain and spinal cord and are called spina bifida or neural tube
defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use
this medicine during pregnancy. These defects can begin in the first month, even before
you know you are pregnant. Other birth defects can happen.
o Birth defects may occur even in children born to women who are not taking any
medicines and do not have other risk factors.
o Taking folic acid supplements before getting pregnant and during early pregnancy can
lower the chance of having a baby with a neural tube defect.
o If you take Depakote or Depakene during pregnancy for any medical condition, your
child is at risk for having a lower IQ.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o There may be other medicines to treat your condition that have a lower chance of causing
birth defects and decreased IQ in your child.
o Women who are pregnant must not take Depakote or Depakene to prevent migraine
headaches.
o All women of childbearing age should talk to their healthcare provider about using
other possible treatments instead of Depakote or Depakene. If the decision is made
to use Depakote or Depakene, you should use effective birth control (contraception).
o Tell your healthcare provider right away if you become pregnant while taking Depakote
or Depakene. You and your healthcare provider should decide if you will continue to take
Depakote or Depakene while you are pregnant.
o Pregnancy Registry: If you become pregnant while taking Depakote or Depakene, talk
to your healthcare provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of antiepileptic drugs
during pregnancy.
3. Inflammation of your pancreas that can cause death.
Call your healthcare provider right away if you have any of these symptoms:
o severe stomach pain that you may also feel in your back
o nausea or vomiting that does not go away
4. Like other antiepileptic drugs, Depakote or Depakene may cause suicidal thoughts or
actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these symptoms, especially if
they are new, worse, or worry you:
o thoughts about suicide or dying
o attempts to commit suicide
o new or worse depression
o new or worse anxiety
o feeling agitated or restless
o panic attacks
o trouble sleeping (insomnia)
o new or worse irritability
o acting aggressive, being angry, or violent
o acting on dangerous impulses
o an extreme increase in activity and talking (mania)
o other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
o Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or
feelings.
o Keep all follow-up visits with your healthcare provider as scheduled.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call your healthcare provider between visits as needed, especially if you are worried about
symptoms.
Do not stop Depakote or Depakene without first talking to a healthcare provider.
Stopping Depakote or Depakene suddenly can cause serious problems. Stopping a seizure
medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status
epilepticus).
Suicidal thoughts or actions can be caused by things other than medicines. If you have
suicidal thoughts or actions, your healthcare provider may check for other causes.
What are Depakote and Depakene?
Depakote and Depakene come in different dosage forms with different usages.
Depakote Tablets and Depakote Extended Release Tablets are prescription medicines used:
• to treat manic episodes associated with bipolar disorder
• alone or with other medicines to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
• to prevent migraine headaches
Depakene (solution and liquid capsules) and Depakote Sprinkles are prescription medicines used
alone or with other medicines, to treat:
• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types
Who should not take Depakote or Depakene?
Do not take Depakote or Depakene if you:
• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g.
Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients
in Depakote or Depakene. See the end of this leaflet for a complete list of ingredients in
Depakote and Depakene.
• have a genetic problem called urea cycle disorder
• are pregnant for the prevention of migraine headaches
What should I tell my healthcare provider before taking Depakote or Depakene?
Before you take Depakote or Depakene, tell your healthcare provider if you:
• have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher
syndrome)
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• drink alcohol
• are pregnant or breastfeeding. Depakote or Depakene can pass into breast milk. Talk to your
healthcare provider about the best way to feed your baby if you take Depakote or Depakene.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short
period of time.
Taking Depakote or Depakene with certain other medicines can cause side effects or affect how
well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and
pharmacist each time you get a new medicine.
How should I take Depakote or Depakene?
• Take Depakote or Depakene exactly as your healthcare provider tells you. Your healthcare
provider will tell you how much Depakote or Depakene to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of Depakote or Depakene without talking to your healthcare
provider.
• Do not stop taking Depakote or Depakene without first talking to your healthcare
provider. Stopping Depakote or Depakene suddenly can cause serious problems.
• Swallow Depakote tablets, Depakote ER tablets or Depakene capsules whole. Do not crush
or chew Depakote tablets, Depakote ER tablets, or Depakene capsules. Tell your healthcare
provider if you can not swallow Depakote or Depakene whole. You may need a different
medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or they may be opened and the
contents may be sprinkled on a small amount of soft food, such as applesauce or pudding.
See the Administration Guide at the end of this Medication Guide for detailed instructions on
how to use Depakote Sprinkle Capsules.
• If you take too much Depakote or Depakene, call your healthcare provider or local Poison
Control Center right away.
What should I avoid while taking Depakote or Depakene?
• Depakote and Depakene can cause drowsiness and dizziness. Do not drink alcohol or take
other medicines that make you sleepy or dizzy while taking Depakote or Depakene, until you
talk with your doctor. Taking Depakote or Depakene with alcohol or drugs that cause
sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how Depakote or
Depakene affects you. Depakote and Depakene can slow your thinking and motor skills.
What are the possible side effects with Depakote or Depakene?
• See “What is the most important information I should know about Depakote or
Depakene?”
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Depakote or Depakene can cause serious side effects including:
• Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth,
teeth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F,
feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering
and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips,
tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or
drink less than you normally would. Tell your doctor if you are not able to eat or drink as you
normally do. Your doctor may start you at a lower dose of Depakote or Depakene.
Call your healthcare provider right away, if you have any of the symptoms listed above.
The common side effects of Depakote and Depakene include:
• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination
These are not all of the possible side effects of Depakote or Depakene. For more information,
ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store Depakote or Depakene?
• Store Depakote Extended Release Tablets between 59°F to 86°F (15°C to 30°C).
• Store Depakote Delayed Release Tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Store Depakene Capsules between 59°F to 77°F (15°C to 25°C).
• Store Depakene Oral Solution below 86°F (30°C).
Keep Depakote or Depakene and all medicines out of the reach of children.
General information about the safe and effective use of Depakote or Depakene
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use Depakote or Depakene for a condition for which it was not prescribed. Do not give
Depakote or Depakene to other people, even if they have the same symptoms that you have. It
may harm them.
This Medication Guide summarizes the most important information about Depakote or
Depakene. If you would like more information, talk with your healthcare provider. You can ask
your pharmacist or healthcare provider for information about Depakote or Depakene that is
written for health professionals.
For more information, go to www.rxabbvie.com or call 1-800-633-9110.
What are the ingredients in Depakote or Depakene?
Depakote
Active ingredient: divalproex sodium
Inactive ingredients:
• Depakote Extended Release Tablets: FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon
dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and
polydextrose.
• Depakote Tablets: cellulosic polymers, diacetylated monoglycerides, povidone,
pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
250 mg tablets: FD&C Yellow No. 6 and iron oxide,
500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide.
• Depakote Sprinkle Capsules: cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1
gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
Depakene:
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Active ingredient: valproic acid
Inactive ingredients:
• Depakene Capsules: corn oil, FD&C Yellow No. 6, gelatin, glycerin, iron oxide,
methylparaben, propylparaben, and titanium dioxide.
• Depakene Oral Solution: FD&C Red No. 40, glycerin, methylparaben, propylparaben,
sorbitol, sucrose, water, and natural and artificial flavors.
Depakote ER:
250 mg is Mfd. by AbbVie LTD, Barceloneta, PR 00617
500 mg is Mfd. by AbbVie Inc., North Chicago, IL 60064 U.S.A. or
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064 U.S.A.
Depakote Tablets:
Mfd. by AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakote Sprinkle Capsules:
AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Capsules:
Mfd. by Banner Pharmacaps, Inc., High Point, NC 27265 U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
Depakene Oral Solution:
Mfd. by AbbVie Inc., North Chicago, IL 60064, U.S.A.
OR by DPT Laboratories, Ltd., San Antonio, TX 78215, U.S.A.
For AbbVie Inc., North Chicago, IL 60064, U.S.A.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
03-A929 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Depacon
safely and effectively. See full prescribing information for Depacon.
Depacon (valproate sodium) for intravenous injection
Initial U.S. Approval: 1996
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning
• Hepatotoxicity, including fatalities, usually during first 6 months of
treatment. Children under the age of two years and patients with
mitochondrial disorders are at higher risk. Monitor patients closely,
and perform serum liver testing prior to therapy and at frequent
intervals thereafter (5.1)
• Fetal Risk, particularly neural tube defects, other major
malformations, and decreased IQ (5.2, 5.3, 5.4)
• Pancreatitis, including fatal hemorrhagic cases (5.5)
-------RECENT MAJOR CHANGES-------
Boxed Warning, Hepatotoxicity 07/2013
Boxed Warning, Fetal Risk 06/2013
Indications and Usage, Important Limitations (1.2) 06/2013
Contraindications, Known or Suspected Mitochondrial Disorders (4) 07/2013
Warnings and Precautions, Hepatotoxicity (5.1) 07/2013
Warnings and Precautions, Birth Defects (5.2) 06/2013
Warnings and Precautions, Decreased IQ (5.3) 06/2013
Warnings and Precautions, Use in Women of Childbearing Potential (5.4)
06/2013
-------INDICATIONS AND USAGE-------
Depacon is an anti-epileptic drug and is indicated as an intravenous alternative
in patients in whom oral administration of valproate products is temporarily
not feasible in the following conditions:
• Monotherapy and adjunctive therapy of complex partial seizures and
simple and complex absence seizures; adjunctive therapy in patients with
multiple seizure types that include absence seizures (1)
-------DOSAGE AND ADMINISTRATION-------
Depacon is intended for intravenous use only.
• Epilepsy
o Complex Partial Seizures in Adults and Children 10 years of age or
older: Initial dose is 10 to 15 mg/kg/day, increasing at 1 week
intervals by 5 to10 mg/kg/day to achieve optimal clinical response.
Maximum recommended dose is 60 mg/kg/day (2.1).
o Simple and Complex Absence Seizures: Initial dose is 10 to 15
mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to
achieve optimal clinical response. Maximum recommended dose is
60 mg/kg/day (2.1).
-------DOSAGE FORMS AND STRENGTHS-------
Injection: 100 mg per mL in a 5 mL single dose vial (3)
-------CONTRAINDICATIONS-------
• Hepatic disease or significant hepatic dysfunction (4, 5.1)
• Known mitochondrial disorders caused by mutations in mitochondrial
DNA polymerase γ (POLG) (4, 5.1)
• Suspected POLG-related disorder in children under two years of age (4,
5.1)
• Known hypersensitivity to the drug (4, 5.11)
• Urea cycle disorders (4, 5.6)
-------WARNINGS AND PRECAUTIONS-------
• Hepatotoxicity; evaluate high risk populations and monitor serum liver
tests (5.1)
• Birth defects and decreased IQ following in utero exposure; only use to
treat pregnant women with epilepsy if other medications are unacceptable;
should not be administered to a woman of childbearing potential unless
essential (5.2, 5.3, 5.4)
• Pancreatitis; Depacon should ordinarily be discontinued (5.5)
• Thrombocytopenia; monitor platelet counts and coagulation tests (5.7)
• Hyperammonemia and hyperammonemic encephalopathy; measure
ammonia level if unexplained lethargy and vomiting or changes in mental
status (5.8, 5.9)
• Hypothermia; Hypothermia has been reported during valproate therapy
with or without associated hyperammonemia. This adverse reaction can
also occur in patients using concomitant topiramate (5.10)
• Multi-organ hypersensitivity reaction; discontinue Depacon (5.11)
• Somnolence in the elderly can occur. Depacon dosage should be increased
slowly and with regular monitoring for fluid and nutritional intake (5.13)
-------ADVERSE REACTIONS-------
Adverse reactions occurring in at least 5% of patients treated with Depakote in
Monotherapy or Adjunctive Complex Partial Seizures Trials:
• Abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia,
asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia,
dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu
syndrome, headache, infection, insomnia, nausea, nervousness,
nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking
abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain,
weight loss (6.1)
Additional Adverse Reactions not included above that occurred in > 0.5% of
patients treated with Depacon:
• Chest pain, euphoria, hypesthesia, injection site inflammation, injection
site pain, injection site reaction, pain, sweating, taste perversion,
vasodilation (6)
Additional adverse reactions not included above that occurred in other clinical
trials with Depakote:
• Accidental injury, back pain, increased appetite, rash (6)
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-------DRUG INTERACTIONS-------
• Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine,
phenobarbital, primidone, rifampin) can increase valproate clearance,
while enzyme inhibitors (e.g., felbamate) can decrease valproate
clearance. Therefore increased monitoring of valproate and concomitant
drug concentrations and dosage adjustment are indicated whenever
enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1)
• Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations is
recommended (7.1)
• Co-administration of valproate can affect the pharmacokinetics of other
drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting
their metabolism or protein binding displacement (7.2)
• Dosage adjustment of amitryptyline/nortryptyline, warfarin, and
zidovudine may be necessary if used concomitantly with Depacon (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.9, 7.3)
-------USE IN SPECIFIC POPULATIONS-------
• Pregnancy: Depacon can cause congenital malformations including neural
tube defects and decreased IQ. (5.2, 5.3 8.1)
• Pediatric: Children under the age of two years are at considerably higher
risk of fatal hepatotoxicity (5.1, 8.4)
• Geriatric: Reduce starting dose, increase dosage more slowly; monitor
fluid and nutritional intake, and somnolence (5.13, 8.5)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LIFE THREATENING ADVERSE REACTIONS
3 DOSAGE FORMS AND STRENGTHS
1 INDICATIONS AND USAGE
4 CONTRAINDICATIONS
1.1 Epilepsy
5 WARNINGS AND PRECAUTIONS
1.2 Important Limitations
5.1 Hepatotoxicity
2 DOSAGE AND ADMINISTRATION
5.2 Birth Defects
2.1 Epilepsy
5.3 Decreased IQ Following in utero Exposure
2.2 General Dosing Advice
5.4 Use in Women of Childbearing Potential
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5.5 Pancreatitis
5.6 Urea Cycle Disorders
5.7 Thrombocytopenia
5.8 Hyperammonemia
5.9 Hyperammonemia and Encephalopathy associated with Concomitant
Topiramate Use
5.10 Hypothermia
5.11 Multi-Organ Hypersensitivity Reactions
5.12 Interaction with Carbapenem Antibiotics
5.13 Somnolence in the Elderly
5.14 Post-traumatic Seizures
5.15 Monitoring: Drug Plasma Concentration
5.16 Effect on Ketone and Thyroid Function Tests
5.17 Effect on HIV and CMV Viruses Replication
6 ADVERSE REACTIONS
6.1 Epilepsy
6.2 Mania
6.3 Migraine
6.4 Other Patient Populations
7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
7.2 Effects of Valproate on Other Drugs
7.3 Topiramate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Epilepsy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
17.2 Pancreatitis
17.3 Birth Defects and Decreased IQ
17.4 Hyperammonemia
17.5 CNS Depression
17.6 Multi-Organ Hypersensitivity Reactions
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
General Population: Hepatic failure resulting in fatalities has occurred in patients receiving
valproate and its derivatives. These incidents usually have occurred during the first six
months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific
symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In
patients with epilepsy, a loss of seizure control may also occur. Patients should be
monitored closely for appearance of these symptoms. Serum liver tests should be
performed prior to therapy and at frequent intervals thereafter, especially during the first
six months [see Warnings and Precautions (5.1)].
Children under the age of two years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental
retardation, and those with organic brain disease. When Depacon is used in this patient
group, it should be used with extreme caution and as a sole agent. The benefits of therapy
should be weighed against the risks. The incidence of fatal hepatotoxicity decreases
considerably in progressively older patient groups.
Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute
liver failure and resultant deaths in patients with hereditary neurometabolic syndromes
caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.
Alpers Huttenlocher Syndrome). Depacon is contraindicated in patients known to have
mitochondrial disorders caused by POLG mutations and children under two years of age
who are clinically suspected of having a mitochondrial disorder [see Contraindications (4)].
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depacon should only be used after other anticonvulsants have
failed. This older group of patients should be closely monitored during treatment with
Depacon for the development of acute liver injury with regular clinical assessments and
serum liver testing. POLG mutation screening should be performed in accordance with
current clinical practice [see Warnings and Precautions (5.1)].
Fetal Risk
Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,
spina bifida). In addition, valproate can cause decreased IQ scores following in utero
exposure.
Valproate should only be used to treat pregnant women with epilepsy if other medications
have failed to control their symptoms or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless the drug
is essential to the management of her medical condition. This is especially important when
valproate use is considered for a condition not usually associated with permanent injury or
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death (e.g., migraine). Women should use effective contraception while using valproate [see
Warnings and Precautions (5.2, 5.3, 5.4) and Patient Counseling Information (17)].
Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults
receiving valproate. Some of the cases have been described as hemorrhagic with a rapid
progression from initial symptoms to death. Cases have been reported shortly after initial
use as well as after several years of use. Patients and guardians should be warned that
abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should
ordinarily be discontinued. Alternative treatment for the underlying medical condition
should be initiated as clinically indicated [see Warnings and Precautions (5.5)].
1 INDICATIONS AND USAGE
1.1 Epilepsy
Depacon is indicated as an intravenous alternative in patients for whom oral administration of
valproate products is temporarily not feasible in the following conditions:
Depacon is indicated as monotherapy and adjunctive therapy in the treatment of patients with
complex partial seizures that occur either in isolation or in association with other types of
seizures. Depacon is also indicated for use as sole and adjunctive therapy in the treatment of
patients with simple and complex absence seizures, and adjunctively in patients with multiple
seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness
accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precautions (5.1) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations
Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital
malformations, which may occur very early in pregnancy, valproate should not be administered
to a woman of childbearing potential unless the drug is essential to the management of her
medical condition [see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations
(8.1), and Patient Counseling Information (17.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Epilepsy
Depacon is for intravenous use only.
Use of Depacon for periods of more than 14 days has not been studied. Patients should be
switched to oral valproate products as soon as it is clinically feasible.
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Depacon should be administered as a 60 minute infusion (but not more than 20 mg/min) with the
same frequency as the oral products, although plasma concentration monitoring and dosage
adjustments may be necessary.
In one clinical safety study, approximately 90 patients with epilepsy and with no measurable
plasma levels of valproate were given single infusions of Depacon (up to 15 mg/kg and mean
dose of 1184 mg) over 5-10 minutes (1.5-3.0 mg/kg/min). Patients generally tolerated the more
rapid infusions well [see Adverse Reactions (6.1)]. This study was not designed to assess the
effectiveness of these regimens. For pharmacokinetics with rapid infusions, see Clinical
Pharmacology (12.3).
Initial Exposure to Valproate
The following dosage recommendations were obtained from studies utilizing oral divalproex
sodium products.
Complex Partial Seizures
For adults and children 10 years of age or older.
Monotherapy (Initial Therapy)
Depacon has not been systematically studied as initial therapy. Patients should initiate therapy at
10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal
clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60
mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be
measured to determine whether or not they are in the usually accepted therapeutic range (50 to
100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60
mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma
concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of
improved seizure control with higher doses should be weighed against the possibility of a greater
incidence of adverse reactions.
Conversion to Monotherapy
Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10
mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is
achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been
achieved, plasma levels should be measured to determine whether or not they are in the usually
accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of
valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug
(AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction
may be started at initiation of Depacon therapy, or delayed by 1 to 2 weeks if there is a concern
that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the
concomitant AED can be highly variable, and patients should be monitored closely during this
period for increased seizure frequency.
Adjunctive Therapy
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Depacon may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage
may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical
response has not been achieved, plasma levels should be measured to determine whether or not
they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation
regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total
daily dose exceeds 250 mg, it should be given in divided doses.
In a study of adjunctive therapy for complex partial seizures in which patients were receiving
either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or
phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact
with these or other concurrently administered AEDs as well as other drugs, periodic plasma
concentration determinations of concomitant AEDs are recommended during the early course of
therapy [see Drug Interactions (7)].
Simple and Complex Absence Seizures
The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10
mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum
recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given
in divided doses.
A good correlation has not been established between daily dose, serum concentrations, and
therapeutic effect. However, therapeutic valproate serum concentration for most patients with
absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be
controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].
As the Depacon dosage is titrated upward, blood concentrations of phenobarbital and/or
phenytoin may be affected [see Drug Interactions (7.2)].
Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life.
Replacement Therapy
When switching from oral valproate products, the total daily dose of Depacon should be
equivalent to the total daily dose of the oral valproate product [see Clinical Pharmacology (12)],
and should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same
frequency as the oral products, although plasma concentration monitoring and dosage
adjustments may be necessary. Patients receiving doses near the maximum recommended daily
dose of 60 mg/kg/day, particularly those not receiving enzyme-inducing drugs, should be
monitored more closely. If the total daily dose exceeds 250 mg, it should be given in a divided
regimen. There is no experience with more rapid infusions in patients receiving Depacon as
replacement therapy. However, the equivalence shown between Depacon and oral valproate
products (Depakote) at steady state was only evaluated in an every 6 hour regimen. Whether,
when Depacon is given less frequently (i.e., twice or three times a day), trough levels fall below
those that result from an oral dosage form given via the same regimen, is unknown. For this
reason, when Depacon is given twice or three times a day, close monitoring of trough plasma
levels may be needed.
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2.2 General Dosing Advice
Dosing in Elderly Patients
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to
somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should
be increased more slowly and with regular monitoring for fluid and nutritional intake,
dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of
valproate should be considered in patients with decreased food or fluid intake and in patients
with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of
both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific
Populations (8.5) and Clinical Pharmacology (12.3)].
Dose-Related Adverse Reactions
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia)
may be dose-related. The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see
Warnings and Precautions (5.7)]. The benefit of improved therapeutic effect with higher doses
should be weighed against the possibility of a greater incidence of adverse reactions.
Administration
Rapid infusion of Depacon has been associated with an increase in adverse reactions. There is
limited experience with infusion times of less than 60 minutes or rates of infusion > 20 mg/min
in patients with epilepsy [see Adverse Reactions (6)].
Depacon should be administered intravenously as a 60 minute infusion, as noted above. It should
be diluted with at least 50 mL of a compatible diluent. Any unused portion of the vial contents
should be discarded.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Compatibility and Stability
Depacon was found to be physically compatible and chemically stable in the following
parenteral solutions for at least 24 hours when stored in glass or polyvinyl chloride (PVC) bags
at controlled room temperature 15-30°C (59-86°F).
• dextrose (5%) injection, USP
• sodium chloride (0.9%) injection, USP
• lactated ringer's injection, USP
3 DOSAGE FORMS AND STRENGTHS
Depacon (valproate sodium injection), equivalent to 100 mg of valproic acid per mL, is a clear,
colorless solution in 5 mL single-dose vials, available in trays of 10 vials.
Recommended storage: Store vials at controlled room temperature 15-30°C (59-86°F). No
preservatives have been added. Unused portion of container should be discarded.
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4 CONTRAINDICATIONS
• Depacon should not be administered to patients with hepatic disease or significant hepatic
dysfunction [see Warnings and Precautions (5.1)].
• Depacon is contraindicated in patients known to have mitochondrial disorders caused by
mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome)
and children under two years of age who are suspected of having a POLG-related disorder
[see Warnings and Precautions (5.1)].
• Depacon is contraindicated in patients with known hypersensitivity to the drug [see
Warnings and Precautions (5.11)].
• Depacon is contraindicated in patients with known urea cycle disorders [see Warnings and
Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
General Information on Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents
usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity
may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur.
Patients should be monitored closely for appearance of these symptoms. Serum liver tests should
be performed prior to therapy and at frequent intervals thereafter, especially during the first six
months of valproate therapy. However, physicians should not rely totally on serum biochemistry
since these tests may not be abnormal in all instances, but should also consider the results of
careful interim medical history and physical examination.
Caution should be observed when administering valproate products to patients with a prior
history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and
those with organic brain disease may be at particular risk. See below, “Patients with Known or
Suspected Mitochondrial Disease.”
Experience has indicated that children under the age of two years are at a considerably increased
risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions.
When Depacon is used in this patient group, it should be used with extreme caution and as a sole
agent. The benefits of therapy should be weighed against the risks. Use of Depacon has not been
studied in children below the age of 2 years. In progressively older patient groups experience in
epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably.
Patients with Known or Suspected Mitochondrial Disease
Depacon is contraindicated in patients known to have mitochondrial disorders caused by POLG
mutations and children under two years of age who are clinically suspected of having a
mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and
liver-related deaths have been reported in patients with hereditary neurometabolic syndromes
caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-
Reference ID: 3520933
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Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the
reported cases of liver failure in patients with these syndromes have been identified in children
and adolescents.
POLG-related disorders should be suspected in patients with a family history or suggestive
symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy,
refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays,
psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia,
opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be
performed in accordance with current clinical practice for the diagnostic evaluation of such
disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with
autosomal recessive POLG-related disorders.
In patients over two years of age who are clinically suspected of having a hereditary
mitochondrial disease, Depacon should only be used after other anticonvulsants have failed. This
older group of patients should be closely monitored during treatment with Depacon for the
development of acute liver injury with regular clinical assessments and serum liver test
monitoring.
The drug should be discontinued immediately in the presence of significant hepatic dysfunction,
suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of
discontinuation of drug [see Boxed Warning and Contraindications (4)].
5.2 Birth Defects
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data
show that maternal valproate use can cause neural tube defects and other structural abnormalities
(e.g., craniofacial defects, cardiovascular malformations and malformations involving various
body systems). The rate of congenital malformations among babies born to mothers using
valproate is about four times higher than the rate among babies born to epileptic mothers using
other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to
conception and during the first trimester of pregnancy decreases the risk for congenital neural
tube defects in the general population.
5.3 Decreased IQ Following in utero Exposure
Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological
studies have indicated that children exposed to valproate in utero have lower cognitive test
scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic
drugs. The largest of these studies1 is a prospective cohort study conducted in the United States
and United Kingdom that found that children with prenatal exposure to valproate (n=62) had
lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other
antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]),
carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not
known when during pregnancy cognitive effects in valproate-exposed children occur. Because
the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the
risk for decreased IQ was related to a particular time period during pregnancy could not be
assessed.
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Although all of the available studies have methodological limitations, the weight of the evidence
supports the conclusion that valproate exposure in utero can cause decreased IQ in children.
In animal studies, offspring with prenatal exposure to valproate had malformations similar to
those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific
Populations (8.1)].
Women with epilepsy who are pregnant or who plan to become pregnant should not be treated
with valproate unless other treatments have failed to provide adequate symptom control or are
otherwise unacceptable. In such women, the benefits of treatment with valproate during
pregnancy may still outweigh the risks.
5.4 Use in Women of Childbearing Potential
Because of the risk to the fetus of decreased IQ and major congenital malformations (including
neural tube defects), which may occur very early in pregnancy, valproate should not be
administered to a woman of childbearing potential unless the drug is essential to the management
of her medical condition. This is especially important when valproate use is considered for a
condition not usually associated with permanent injury or death (e.g., migraine). Women should
use effective contraception while using valproate. Women who are planning a pregnancy should
be counseled regarding the relative risks and benefits of valproate use during pregnancy, and
alternative therapeutic options should be considered for these patients [see Boxed Warning and
Use in Specific Populations (8.1)].
To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate
status epilepticus with resulting maternal and fetal hypoxia and threat to life.
Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic
acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
5.5 Pancreatitis
Cases of life-threatening pancreatitis have been reported in both children and adults receiving
valproate. Some of the cases have been described as hemorrhagic with rapid progression from
initial symptoms to death. Some cases have occurred shortly after initial use as well as after
several years of use. The rate based upon the reported cases exceeds that expected in the general
population and there have been cases in which pancreatitis recurred after rechallenge with
valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416
patients, representing 1044 patient-years experience. Patients and guardians should be warned
that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that
require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be
discontinued. Alternative treatment for the underlying medical condition should be initiated as
clinically indicated [see Boxed Warning].
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5.6 Urea Cycle Disorders
Valproate sodium is contraindicated in patients with known urea cycle disorders (UCD).
Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of
valproate therapy in patients with urea cycle disorders, a group of uncommon genetic
abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of
valproate therapy, evaluation for UCD should be considered in the following patients: 1) those
with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein
load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or
history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy,
episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family
history of UCD or a family history of unexplained infant deaths (particularly males); 4) those
with other signs or symptoms of UCD. Patients who develop symptoms of unexplained
hyperammonemic encephalopathy while receiving valproate therapy should receive prompt
treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea
cycle disorders [see Contraindications (4) and Warnings and Precautions (5.9)].
5.7 Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia may
be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126
patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of
platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with
return of platelet counts to normal. In the remaining patients, platelet counts normalized with
continued treatment. In this study, the probability of thrombocytopenia appeared to increase
significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL
(males). The therapeutic benefit which may accompany the higher doses should therefore be
weighed against the possibility of a greater incidence of adverse effects.
Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet
aggregation, and abnormal coagulation parameters (e.g., low fibrinogen), platelet counts and
coagulation tests are recommended before initiating therapy and at periodic intervals. It is
recommended that patients receiving Depacon be monitored for platelet count and coagulation
parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of
hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
5.8 Hyperammonemia
Hyperammonemia has been reported in association with valproate therapy and may be present
despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or
changes in mental status, hyperammonemic encephalopathy should be considered and an
ammonia level should be measured. Hyperammonemia should also be considered in patients who
present with hypothermia [see Warnings and Precautions (5.10)]. If ammonia is increased,
valproate therapy should be discontinued. Appropriate interventions for treatment of
hyperammonemia should be initiated, and such patients should undergo investigation for
underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6,
5.9)].
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Asymptomatic elevations of ammonia are more common and when present, require close
monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate
therapy should be considered.
5.9 Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use
Concomitant administration of topiramate and valproate has been associated with
hyperammonemia with or without encephalopathy in patients who have tolerated either drug
alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in
level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can
also be a manifestation of hyperammonemia [see Warnings and Precautions (5.10)]. In most
cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is
not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated
with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic
mitochondrial activity may be at an increased risk for hyperammonemia with or without
encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate
existing defects or unmask deficiencies in susceptible persons. In patients who develop
unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy
should be considered and an ammonia level should be measured [see Contraindications (4) and
Warnings and Precautions (5.8)].
5.10 Hypothermia
Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has
been reported in association with valproate therapy both in conjunction with and in the absence
of hyperammonemia. This adverse reaction can also occur in patients using concomitant
topiramate with valproate after starting topiramate treatment or after increasing the daily dose of
topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in
patients who develop hypothermia, which may be manifested by a variety of clinical
abnormalities including lethargy, confusion, coma, and significant alterations in other major
organ systems such as the cardiovascular and respiratory systems. Clinical management and
assessment should include examination of blood ammonia levels.
5.11 Multi-Organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to
the initiation of valproate therapy in adult and pediatric patients (median time to detection 21
days: range 1 to 40 days). Although there have been a limited number of reports, many of these
cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of
this disorder were diverse; however, patients typically, although not exclusively, presented with
fever and rash associated with other organ system involvement. Other associated manifestations
may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological
abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria,
hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is
suspected, valproate should be discontinued and an alternative treatment started. Although the
existence of cross sensitivity with other drugs that produce this syndrome is unclear, the
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experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be
a possibility.
5.12 Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete
list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of
seizure control. Serum valproate concentrations should be monitored frequently after initiating
carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if
serum valproate concentrations drop significantly or seizure control deteriorates [see Drug
Interactions (7.1)].
5.13 Somnolence in the Elderly
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83
years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly
higher proportion of valproate patients had somnolence compared to placebo, and although not
statistically significant, there was a higher proportion of patients with dehydration.
Discontinuations for somnolence were also significantly higher than with placebo. In some
patients with somnolence (approximately one-half), there was associated reduced nutritional
intake and weight loss. There was a trend for the patients who experienced these events to have a
lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly
patients, dosage should be increased more slowly and with regular monitoring for fluid and
nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or
discontinuation of valproate should be considered in patients with decreased food or fluid intake
and in patients with excessive somnolence [see Dosage and Administration (2.2)].
5.14 Post-traumatic Seizures
A study was conducted to evaluate the effect of IV valproate in the prevention of post-traumatic
seizures in patients with acute head injuries. Patients were randomly assigned to receive either
IV valproate given for one week (followed by oral valproate products for either one or six
months per random treatment assignment) or IV phenytoin given for one week (followed by
placebo). In this study, the incidence of death was found to be higher in the two groups assigned
to valproate treatment compared to the rate in those assigned to the IV phenytoin treatment group
(13% vs. 8.5%, respectively). Many of these patients were critically ill with multiple and/or
severe injuries, and evaluation of the causes of death did not suggest any specific drug-related
causation. Further, in the absence of a concurrent placebo control during the initial week of
intravenous therapy, it is impossible to determine if the mortality rate in the patients treated with
valproate was greater or less than that expected in a similar group not treated with valproate, or
whether the rate seen in the IV phenytoin treated patients was lower than would be expected.
Nonetheless, until further information is available, it seems prudent not to use Depacon in
patients with acute head trauma for the prophylaxis of post-traumatic seizures.
5.15 Monitoring: Drug Plasma Concentration
Since valproate may interact with concurrently administered drugs which are capable of enzyme
induction, periodic plasma concentration determinations of valproate and concomitant drugs are
recommended during the early course of therapy [see Drug Interactions (7)].
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5.16 Effect on Ketone and Thyroid Function Tests
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false
interpretation of the urine ketone test.
There have been reports of altered thyroid function tests associated with valproate. The clinical
significance of these is unknown.
5.17 Effect on HIV and CMV Viruses Replication
There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV
viruses under certain experimental conditions. The clinical consequence, if any, is not known.
Additionally, the relevance of these in vitro findings is uncertain for patients receiving
maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind
when interpreting the results from regular monitoring of the viral load in HIV infected patients
receiving valproate or when following CMV infected patients clinically.
6 ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
studies of another drug and may not reflect the rates observed in practice.
The adverse reactions that can result from Depacon use include all of those associated with oral
forms of valproate. The following describes experience specifically with Depacon. Depacon has
been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and
352 patients with epilepsy, given at doses of 125 to 6,000 mg (total daily dose). A total of 2% of
patients discontinued treatment with Depacon due to adverse reactions. The most common
adverse reactions leading to discontinuation were 2 cases each of nausea/vomiting and elevated
amylase. Other adverse reactions leading to discontinuation were hallucinations, pneumonia,
headache, injection site reaction, and abnormal gait. Dizziness and injection site pain were
observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200
mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate.
The maximum rate of infusion studied was 200 mg/min.
Adverse reactions reported by at least 0.5% of all subjects/patients in clinical trials of Depacon
are summarized in Table 1.
Table 1. Adverse Reactions Reported During Studies of Depacon
Body System/Reaction
N = 463
Body as a Whole
Chest Pain
1.7%
Headache
4.3%
Injection Site Inflammation
0.6%
Injection Site Pain
2.6%
Injection Site Reaction
2.4%
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Pain (unspecified)
1.3%
Cardiovascular
Vasodilation
0.9%
Dermatologic
Sweating
0.9%
Digestive System
Abdominal Pain
1.1%
Diarrhea
0.9%
Nausea
3.2%
Vomiting
1.3%
Nervous System
Dizziness
5.2%
Euphoria
0.9%
Hypesthesia
0.6%
Nervousness
0.9%
Paresthesia
0.9%
Somnolence
1.7%
Tremor
0.6%
Respiratory
Pharyngitis
0.6%
Special Senses
Taste Perversion
1.9%
In a separate clinical safety trial, 112 patients with epilepsy were given infusions of Depacon (up
to 15 mg/kg) over 5 to 10 minutes (1.5-3.0 mg/kg/min). The common adverse reactions (> 2%)
were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%),
and headache (2.7%). While the incidence of these adverse reactions was generally higher than
in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence
(1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache
(4.3%), a direct comparison between the incidence of adverse reactions in the 2 cohorts cannot
be made because of differences in patient populations and study designs.
Ammonia levels have not been systematically studied after IV valproate, so that an estimate of
the incidence of hyperammonemia after IV Depacon cannot be provided. Hyperammonemia with
encephalopathy has been reported in 2 patients after infusions of Depacon.
6.1 Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial
seizures, Depakote (divalproex sodium) was generally well tolerated with most adverse reactions
rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in
the Depakote-treated patients (6%), compared to 1% of placebo-treated patients.
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Table 2 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote
treated patients and for which the incidence was greater than in the placebo group, in the
placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since
patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to
determine whether the following adverse reactions can be ascribed to Depakote alone, or the
combination of Depakote and other antiepilepsy drugs.
Table 2. Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During
Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Reaction
Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
Headache
31
21
Asthenia
27
7
Fever
6
4
Gastrointestinal System
Nausea
48
14
Vomiting
27
7
Abdominal Pain
23
6
Diarrhea
13
6
Anorexia
12
0
Dyspepsia
8
4
Constipation
5
1
Nervous System
Somnolence
27
11
Tremor
25
6
Dizziness
25
13
Diplopia
16
9
Amblyopia/Blurred Vision
12
9
Ataxia
8
1
Nystagmus
8
1
Emotional Lability
6
4
Thinking Abnormal
6
0
Amnesia
5
1
Respiratory System
Flu Syndrome
12
9
Infection
12
6
Bronchitis
5
1
Rhinitis
5
4
Other
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Alopecia
6
1
Weight Loss
6
0
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in
the high dose valproate group, and for which the incidence was greater than in the low dose
group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since
patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is
not possible, in many cases, to determine whether the following adverse reactions can be
ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the
Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1
Body System/Reaction
High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)
Body as a Whole
Asthenia
21
10
Digestive System
Nausea
34
26
Diarrhea
23
19
Vomiting
23
15
Abdominal Pain
12
9
Anorexia
11
4
Dyspepsia
11
10
Hemic/Lymphatic System
Thrombocytopenia
24
1
Ecchymosis
5
4
Metabolic/Nutritional
Weight Gain
9
4
Peripheral Edema
8
3
Nervous System
Tremor
57
19
Somnolence
30
18
Dizziness
18
13
Insomnia
15
9
Nervousness
11
7
Amnesia
7
4
Nystagmus
7
1
Depression
5
4
Respiratory System
Infection
20
13
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Pharyngitis
8
2
Dyspnea
5
1
Skin and Appendages
Alopecia
24
13
Special Senses
Amblyopia/Blurred Vision
8
4
Tinnitus
7
1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose
group and at an equal or greater incidence in the low dose group.
The following additional adverse reactions were reported by greater than 1% but less than 5% of
the 358 patients treated with valproate in the controlled trials of complex partial seizures:
Body as a Whole: Back pain, chest pain, malaise.
Cardiovascular System: Tachycardia, hypertension, palpitation.
Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis,
periodontal abscess.
Hemic and Lymphatic System: Petechia.
Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.
Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.
Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination,
abnormal dreams, personality disorder.
Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.
Skin and Appendages: Rash, pruritus, dry skin.
Special Senses: Taste perversion, abnormal vision, deafness, otitis media.
Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary
frequency.
6.2 Mania
Although Depacon has not been evaluated for safety and efficacy in the treatment of manic
episodes associated with bipolar disorder, the following adverse reactions not listed above were
reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote
(Divalproex Sodium) tablets.
Body as a Whole: Chills, neck pain, neck rigidity.
Cardiovascular System: Hypotension, postural hypotension, vasodilation.
Digestive System: Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System: Arthrosis.
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Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive
dyskinesia, vertigo.
Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
Special Senses: Conjunctivitis, dry eyes, eye pain.
Urogenital: Dysuria.
6.3 Migraine
Although Depacon has not been evaluated for safety and efficacy in the prophylactic treatment of
migraine headaches, the following adverse reactions not listed above were reported by 1% or
more of patients from two placebo-controlled clinical trials of Depakote (Divalproex Sodium)
tablets.
Body as a Whole: Face edema.
Digestive System: Dry mouth, stomatitis.
Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Other Patient Populations
Adverse reactions that have been reported with all dosage forms of valproate from epilepsy
trials, spontaneous reports, and other sources are listed below by body system.
Gastrointestinal: The most commonly reported side effects at the initiation of therapy are nausea,
vomiting, and indigestion. These effects are usually transient and rarely require discontinuation
of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia
with some weight loss and increased appetite with weight gain have also been reported. The
administration of delayed-release divalproex sodium may result in reduction of gastrointestinal
side effects in some patients using oral therapy.
CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most
often in patients receiving combination therapy. Sedation usually abates upon reduction of other
antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache,
nystagmus, diplopia, asterixis, "spots before eyes," dysarthria, dizziness, confusion, hypesthesia,
vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare
cases of coma have occurred in patients receiving valproate alone or in conjunction with
phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after
the introduction of valproate monotherapy without evidence of hepatic dysfunction or
inappropriately high plasma valproate levels. Although recovery has been described following
drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy,
particularly in patients with underlying urea cycle disorders [see Warnings and Precautions
(5.6)].
Several reports have noted reversible cerebral atrophy and dementia in association with valproate
therapy.
Dermatologic: Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema
multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been
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reported including a fatal case in a 6 month old infant taking valproate and several other
concomitant medications. An additional case of toxic epidermal necrosis resulting in death was
reported in a 35 year old patient with AIDS taking several concomitant medications and with a
history of multiple cutaneous drug reactions. Serious skin reactions have been reported with
concomitant administration of lamotrigine and valproate [see Drug Interactions (7)].
Psychiatric: Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and
behavioral deterioration.
Musculoskeletal: Weakness.
Hematologic: Thrombocytopenia and inhibition of the secondary phase of platelet aggregation
may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis,
and frank hemorrhage [see Warnings and Precautions (5.7) and Drug Interactions (7)]. Relative
lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including
macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic
anemia, agranulocytosis, and acute intermittent porphyria.
Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and
appear to be dose-related. Occasionally, laboratory test results include increases in serum
bilirubin and abnormal changes in other liver function tests. These results may reflect potentially
serious hepatotoxicity [see Warnings and Precautions (5.1)].
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and
parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16)].
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect
relationship has not been established.
Pancreatic: Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].
Metabolic: Hyperammonemia [see Warnings and Precautions (5.8)], hyponatremia, and
inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is
undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with
preexistent nonketotic hyperglycinemia.
Genitourinary: Enuresis and urinary tract infection.
Special Senses: Hearing loss, either reversible or irreversible, has been reported; however, a
cause and effect relationship has not been established. Ear pain has also been reported.
Other: Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain,
cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and
hypothermia.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the
offspring of women exposed to valproate during pregnancy.
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7 DRUG INTERACTIONS
7.1 Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,
carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus,
patients on monotherapy will generally have longer half-lives and higher concentrations than
patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on valproate clearance because cytochrome P450 microsomal
mediated oxidation is a relatively minor secondary metabolic pathway compared to
glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or
withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be,
since new interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin
A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with
valproate to pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of
metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin
compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH
valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on
valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and
aspirin are to be co-administered.
Carbapenem Antibiotics
A clinically significant reduction in serum valproic acid concentration has been reported in
patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem this is
not a complete list) and may result in loss of seizure control. The mechanism of this interaction is
not well understood. Serum valproic acid concentrations should be monitored frequently after
initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be
considered if serum valproic acid concentrations drop significantly or seizure control deteriorates
[see Warnings and Precautions (5.12)].
Felbamate
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients
with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from
86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day
increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A
decrease in valproate dosage may be necessary when felbamate therapy is initiated.
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Rifampin
A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5
nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of
valproate. Valproate dosage adjustment may be necessary when it is co-administered with
rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Antacids
A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent
of absorption of valproate.
Chlorpromazine
A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic
patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma
levels of valproate.
Haloperidol
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (200 mg BID) revealed no significant changes in valproate trough
plasma levels.
Cimetidine and Ranitidine
Cimetidine and ranitidine do not affect the clearance of valproate.
7.2 Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
glucuronyl transferases.
The following list provides information about the potential for an influence of valproate co
administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed
medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline
Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males
and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare
postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased
amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely
been associated with toxicity. Monitoring of amitriptyline levels should be considered for
patients taking valproate concomitantly with amitriptyline. Consideration should be given to
lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
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Carbamazepine/carbamazepine-10,11-Epoxide
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11
epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
Clonazepam
The concomitant use of valproate and clonazepam may induce absence status in patients with a
history of absence type seizures.
Diazepam
Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.
Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg)
by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free
diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The
elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide
Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose
of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n = 6) was accompanied
by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total
clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide,
especially along with other anticonvulsants, should be monitored for alterations in serum
concentrations of both drugs.
Lamotrigine
In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine
increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of
lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such
as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with
concomitant lamotrigine and valproate administration. See lamotrigine package insert for details
on lamotrigine dosing with concomitant valproate administration.
Phenobarbital
Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate
(250 mg BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50%
increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-
dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of
valproate.
There is evidence for severe CNS depression, with or without significant elevations of
barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate
therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations
should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
valproate.
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Phenytoin
Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic
metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal
volunteers (n = 7) was associated with a 60% increase in the free fraction of phenytoin. Total
plasma clearance and apparent volume of distribution of phenytoin increased 30% in the
presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin
were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required
by the clinical situation.
Tolbutamide
From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50%
when added to plasma samples taken from patients treated with valproate. The clinical relevance
of this displacement is unknown.
Warfarin
In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The
therapeutic relevance of this is unknown; however, coagulation tests should be monitored if
valproate therapy is instituted in patients taking anticoagulants.
Zidovudine
In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was
decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of
zidovudine was unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
observed
Acetaminophen
Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
Clozapine
In psychotic patients (n = 11), no interaction was observed when valproate was co-administered
with clozapine.
Lithium
Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
Lorazepam
Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of
lorazepam.
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Olanzapine
No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly
with valproate. Co-administration of valproate (500 mg BID) and Olanzapine (5 mg) to healthy
adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine.
Oral Contraceptive Steroids
Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 µg) to 6
women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic
interaction.
7.3 Topiramate
Concomitant administration of valproate and topiramate has been associated with
hyperammonemia with and without encephalopathy [see Contraindications (4) and Warnings
and Precautions (5.8, 5.9)]. Concomitant administration of topiramate with valproate has also
been associated with hypothermia in patients who have tolerated either drug alone. It may be
prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been
reported [see Warnings and Precautions (5.8, 5.10)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D for epilepsy [see Warnings and Precautions (5.2, 5.3)].
Pregnancy Registry
To collect information on the effects of in utero exposure to Depacon, physicians should
encourage pregnant patients taking Depacon to enroll in the North American Antiepileptic Drug
(NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must
be done by the patients themselves. Information on the registry can be found at the website,
http://www.aedpregnancyregistry.org/.
Fetal Risk Summary
All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%),
or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy
for any indication increases the risk of congenital malformations, particularly neural tube defects,
but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular
malformations). The risk of major structural abnormalities is greatest during the first trimester;
however, other serious developmental effects can occur with valproate use throughout
pregnancy. The rate of congenital malformations among babies born to epileptic mothers who
used valproate during pregnancy has been shown to be about four times higher than the rate
among babies born to epileptic mothers who used other anti-seizure monotherapies.
Several published epidemiological studies have indicated that children exposed to valproate in
utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or
to no antiepileptic drugs in utero [see Warnings and Precautions (5.3)].
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In animal studies, offspring with prenatal exposure to valproate had structural malformations
similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations
• Neural tube defects are the congenital malformation most strongly associated with maternal
valproate use. The risk of spina bifida following in utero valproate exposure is generally
estimated as 1-2%, compared to an estimated general population risk for spina bifida of about
0.06 to 0.07% (6 to 7 in 10,000 births).
• Valproate can cause decreased IQ scores in children whose mothers were treated with
valproate during pregnancy.
• Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events,
which may occur very early in pregnancy:
• Valproate should not be administered to a woman of childbearing potential unless the
drug is essential to the management of her medical condition. This is especially important
when valproate use is considered for a condition not usually associated with permanent
injury or death (e.g., migraine).
• Valproate should not be used to treat women with epilepsy who are pregnant or who plan
to become pregnant unless other treatments have failed to provide adequate symptom
control or are otherwise unacceptable. In such women, the benefits of treatment with
valproate during pregnancy may still outweigh the risks. When treating a pregnant
woman or a woman of childbearing potential, carefully consider both the potential risks
and benefits of treatment and provide appropriate counseling.
• To prevent major seizures, women with epilepsy should not discontinue valproate abruptly,
as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat
to life. Even minor seizures may pose some hazard to the developing embryo or fetus.
However, discontinuation of the drug may be considered prior to and during pregnancy in
individual cases if the seizure disorder severity and frequency do not pose a serious threat to
the patient.
• Available prenatal diagnostic testing to detect neural tube and other defects should be offered
to pregnant women using valproate.
• Evidence suggests that folic acid supplementation prior to conception and during the first
trimester of pregnancy decreases the risk for congenital neural tube defects in the general
population. It is not known whether the risk of neural tube defects or decreased IQ in the
offspring of women receiving valproate is reduced by folic acid supplementation. Dietary
folic acid supplementation both prior to conception and during pregnancy should be routinely
recommended for patients using valproate.
• Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions
(5.7)]. A patient who had low fibrinogen when taking multiple anticonvulsants including
valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage.
If valproate is used in pregnancy, the clotting parameters should be monitored carefully.
• Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and
Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have
also been reported following maternal use of valproate during pregnancy.
Data
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Human
There is an extensive body of evidence demonstrating that exposure to valproate in utero
increases the risk of neural tube defects and other structural abnormalities. Based on published
data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the
general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate
exposure has been estimated to be approximately 1 to 2%.
In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following
prenatal valproate exposure were reported among offspring of 149 enrolled women who used
valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases
included craniofacial defects, cardiovascular malformations and malformations of varying
severity involving other body systems. The NAAED Pregnancy Registry has reported a major
malformation rate of 10.7% (95% C.I. 6.3% - 16.9%) in the offspring of women exposed to an
average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500 - 2000
mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic
women who received any other antiepileptic drug monotherapy during pregnancy was 2.9%
(95% C.I. 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation
(Odds Ratio 4.0; 95% C.I. 2.1 to 7.4) following valproate exposure in utero compared to the risk
following exposure in utero to any other antiepileptic drug monotherapy.
Published epidemiological studies have indicated that children exposed to valproate in utero
have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no
antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted
in the United States and United Kingdom that found that children with prenatal exposure to
valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal
exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108
[95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I.
104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed
children occur. Because the women in this study were exposed to antiepileptic drugs throughout
pregnancy, whether the risk for decreased IQ was related to a particular time period during
pregnancy could not be assessed.
Although all of the available studies have methodological limitations, the weight of the evidence
supports a causal association between valproate exposure in utero and subsequent adverse effects
on cognitive development.
There are published case reports of fatal hepatic failure in offspring of women who used
valproate during pregnancy.
Animal
In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates
of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred
following treatment of pregnant animals with valproate during organogenesis at clinically
relevant doses (calculated on a body surface area basis). Valproate induced malformations of
multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to
other malformations, fetal neural tube defects have been reported following valproate
administration during critical periods of organogenesis, and the teratogenic response correlated
with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and
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social interaction deficits) and brain histopathological changes have also been reported in mice
and rat offspring exposed prenatally to clinically relevant doses of valproate.
8.3 Nursing Mothers
Valproate is excreted in human milk. Caution should be exercised when valproate is
administered to a nursing woman.
8.4 Pediatric Use
Experience with oral valproate has indicated that pediatric patients under the age of two years are
at a considerably increased risk of developing fatal hepatotoxicity, especially those with the
aforementioned conditions [see Boxed Warning]. The safety of Depacon has not been studied in
individuals below the age of 2 years. If a decision is made to use Depacon in this age group, it
should be used with extreme caution and as a sole agent. The benefits of therapy should be
weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the
incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.
Younger children, especially those receiving enzyme-inducing drugs, will require larger
maintenance doses to attain targeted total and unbound valproate concentrations.
The variability in free fraction limits the clinical usefulness of monitoring total serum valproic
acid concentrations. Interpretation of valproic acid concentrations in children should include
consideration of factors that affect hepatic metabolism and protein binding.
Pediatric Clinical Trials
No unique safety concerns were identified in the 35 patients age 2 to 17 years who received
Depacon in clinical trials.
One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in
the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of
Depakote in pediatric patients were shown to be comparable to those in adults [see Adverse
Reactions (6)].
Juvenile Animal Toxicology
In studies of valproate in immature animals, toxic effects not observed in adult animals included
retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and
nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods.
The no-effect dose for these findings was less than the maximum recommended human dose on a
mg/m2 basis.
8.5 Geriatric Use
No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of
mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%)
were greater than 65 years of age. A higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was
occasionally associated with the latter two events. It is not clear whether these events indicate
additional risk or whether they result from preexisting medical illness and concomitant
medication use among these patients.
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A study of elderly patients with dementia revealed drug related somnolence and discontinuation
for somnolence [see Warnings and Precautions (5.13)]. The starting dose should be reduced in
these patients, and dosage reductions or discontinuation should be considered in patients with
excessive somnolence [see Dosage and Administration (2.2)].
No unique safety concerns were identified in the 21 patients > 65 years of age receiving Depacon
in clinical trials.
10 OVERDOSAGE
Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities
have been reported; however patients have recovered from valproate serum concentrations as
high as 2120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or
tandem hemodialysis plus hemoperfusion may result in significant removal of drug. General
supportive measures should be applied with particular attention to the maintenance of adequate
urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepilepsy effects of valproate, it should
be used with caution in patients with epilepsy.
11 DESCRIPTION
Depacon (valproate sodium) is the sodium salt of valproic acid designated as sodium 2
propylpentanoate. Valproate sodium has the following structure:
Valproate sodium has a molecular weight of 166.2. It occurs as an essentially white and odorless,
crystalline, deliquescent powder.
Depacon solution is available in 5 mL single-dose vials for intravenous injection. Each mL
contains valproate sodium equivalent to 100 mg valproic acid, edetate disodium 0.40 mg, and
water for injection to volume. The pH is adjusted to 7.6 with sodium hydroxide and/or
hydrochloric acid. The solution is clear and colorless.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Depacon exists as the valproate ion in the blood. The mechanisms by which valproate exerts its
therapeutic effects have not been established. It has been suggested that its activity in epilepsy is
related to increased brain concentrations of gamma-aminobutyric acid (GABA).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented.
One contributing factor is the nonlinear, concentration dependent protein binding of valproate
which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide
a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the
free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher
than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with
hepatic and renal diseases.
Epilepsy
The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total
valproate, although some patients may be controlled with lower or higher plasma concentrations.
Equivalent doses of Depacon and Depakote (divalproex sodium) yield equivalent plasma levels
of the valproate ion [see Clinical Pharmacology (12.3)].
12.3 Pharmacokinetics
Bioavailability
Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result
in equivalent Cmax, Cmin, and total systemic exposure to the valproate ion when the IV valproate
is administered as a 60 minute infusion. However, the rate of valproate ion absorption may vary
with the formulation used. These differences should be of minor clinical importance under the
steady state conditions achieved in chronic use in the treatment of epilepsy.
Administration of Depakote (divalproex sodium) tablets and IV valproate (given as a one hour
infusion), 250 mg every 6 hours for 4 days to 18 healthy male volunteers resulted in equivalent
AUC, Cmax, Cmin at steady state, as well as after the first dose. The Tmax after IV Depacon occurs
at the end of the one hour infusion, while the Tmax after oral dosing with Depakote occurs at
approximately 4 hours. Because the kinetics of unbound valproate are linear, bioequivalence
between Depacon and Depakote up to the maximum recommended dose of 60 mg/kg/day can be
assumed. The AUC and Cmax resulting from administration of IV valproate 500 mg as a single
one hour infusion and a single 500 mg dose of Depakene syrup to 17 healthy male volunteers
were also equivalent.
Patients maintained on valproic acid doses of 750 mg to 4250 mg daily (given in divided doses
every 6 hours) as oral Depakote (divalproex sodium) alone (n = 24) or with another stabilized
antiepileptic drug [carbamazepine (n = 15), phenytoin (n = 11), or phenobarbital (n = 1)],
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showed comparable plasma levels for valproic acid when switching from oral Depakote to IV
valproate (1-hour infusion).
Eleven healthy volunteers were given single infusions of 1000 mg IV valproate over 5, 10, 30,
and 60 minutes in a 4-period crossover study. Total valproate concentrations were measured;
unbound concentrations were not measured. After the 5 minute infusions (mean rate of 2.8
mg/kg/min), mean Cmax was 145 ± 32 mcg/mL, while after the 60 minute infusions, mean Cmax
was 115 ± 8 mcg/mL. Ninety to 120 minutes after infusion initiation, total valproate
concentrations were similar for all 4 rates of infusion. Because protein binding is nonlinear at
higher total valproate concentrations, the corresponding increase in unbound Cmax at faster
infusion rates will be greater.
Distribution
Protein Binding
The plasma protein binding of valproate is concentration dependent and the free fraction
increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of
valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with
renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may
displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide)
(see Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of
valproate with other drugs).
CNS Distribution
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in
plasma (about 10% of total concentration).
Metabolism
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50%
of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation
is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually,
less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an
administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does
not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and
11 L/1.73 m2, respectively. Mean terminal half-life for valproate monotherapy after an
intravenous infusion of 1,000 mg was 16 ± 3.0 hours.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic
metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs
(carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of
these changes in valproate clearance, monitoring of antiepileptic concentrations should be
intensified whenever concomitant antiepileptics are introduced or withdrawn.
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Special Populations
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate
valproate compared to older children and adults. This is a result of reduced clearance (perhaps
due to delay in development of glucuronosyltransferase and other enzyme systems involved in
valproate elimination) as well as increased volume of distribution (in part due to decreased
plasma protein binding). For example, in one study, the half-life in children under 10 days
ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2
months.
Children
Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed
on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have
pharmacokinetic parameters that approximate those of adults.
Elderly
The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been
shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is
reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be
reduced in the elderly [see Dosage and Administration (2.2)].
Effect of Sex
There are no differences in the body surface area adjusted unbound clearance between males and
females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free
valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute
hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased
from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and
larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total
concentrations may be misleading since free concentrations may be substantially elevated in
patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed
Warning, Contraindications (4), and Warnings and Precautions (5.1)].
Renal Disease
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients
with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically
reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be
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necessary in patients with renal failure. Protein binding in these patients is substantially reduced;
thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than
the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings
were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving
valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving
valproate. The significance of these findings for humans is unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant
lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo
cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been
reported in a study of epileptic children taking valproate, but this association was not observed in
another study conducted in adults. There is some evidence that increased SCE frequencies may
be associated with epilepsy. The biological significance of an increase in SCE frequency is not
known.
Fertility
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced
spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats
(approximately equivalent to or greater than the maximum recommended human dose (MRHD)
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or
greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses
of valproate up to 350 mg/kg/day (approximately equal to the MRHD dose on a mg/m2 basis) for
60 days. The effect of valproate on testicular development and on sperm production and fertility
in humans is unknown.
14 CLINICAL STUDIES
The studies described in the following section were conducted with oral divalproex sodium
products.
14.1 Epilepsy
The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur
in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy),
144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of
monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma
concentrations within the "therapeutic range" were randomized to receive, in addition to their
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original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be
followed for a total of 16 weeks. The following Table presents the findings.
Table 4. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment
Number of Patients
Baseline Incidence
Experimental
Incidence
Depakote
75
16.0
8.9*
Placebo
69
14.5
11.5
* Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05
level.
Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive
therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure
frequency), while a negative percent reduction indicates worsening. Thus, in a display of this
type, the curve for an effective treatment is shifted to the left of the curve for placebo. This
Figure shows that the proportion of patients achieving any particular level of improvement was
consistently higher for valproate than for placebo. For example, 45% of patients treated with
valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients
treated with placebo.
Figure 1
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The second study assessed the capacity of valproate to reduce the incidence of CPS when
administered as the sole AED. The study compared the incidence of CPS among patients
randomized to either a high or low dose treatment arm. Patients qualified for entry into the
randomized comparison phase of this study only if 1) they continued to experience 2 or more
CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an
AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a
successful transition over a two week interval to valproate. Patients entering the randomized
phase were then brought to their assigned target dose, gradually tapered off their concomitant
AED and followed for an interval as long as 22 weeks. Less than 50% of the patients
randomized, however, completed the study. In patients converted to Depakote monotherapy, the
mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low
dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-
randomization assessment.
Table 5. Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients
Baseline Incidence
Randomized Phase
Incidence
High dose Depakote
131
13.2
10.7*
Low dose Depakote
134
14.2
13.8
* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤
0.05 level.
Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in
complex partial seizure rates was at least as great as that indicated on the Y axis in the
monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in
seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of
this type, the curve for a more effective treatment is shifted to the left of the curve for a less
effective treatment. This Figure shows that the proportion of patients achieving any particular
level of reduction was consistently higher for high dose valproate than for low dose valproate.
For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone
monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a
reduction in complex partial seizure rates compared to 54% of patients receiving low dose
valproate.
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 2
15 REFERENCES
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive
outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology
2013; 12 (3):244-252.
16 HOW SUPPLIED/STORAGE AND HANDLING
Depacon (valproate sodium injection), equivalent to 100 mg of valproic acid per mL, is a clear,
colorless solution in 5 mL single-dose vials, available in trays of 10 vials (NDC 0074-1564-10).
Recommended storage: Store vials at controlled room temperature 15-30°C (59-86°F). No
preservatives have been added. Unused portion of container should be discarded.
17 PATIENT COUNSELING INFORMATION
17.1 Hepatotoxicity
Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia,
and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical
evaluation promptly [see Warnings and Precautions (5.1)].
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17.2 Pancreatitis
Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be
symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see
Warnings and Precautions (5.5)].
17.3 Birth Defects and Decreased IQ
Inform pregnant women and women of childbearing potential that use of valproate during
pregnancy increases the risk of birth defects and decreased IQ in children who were exposed.
Advise women to use effective contraception while using valproate. When appropriate, counsel
these patients about alternative therapeutic options. This is particularly important when valproate
use is considered for a condition not usually associated with permanent injury or death [see
Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific Populations (8.1)].
Advise women of childbearing potential to discuss pregnancy planning with their doctor and to
contact their doctor immediately if they think they are pregnant.
17.4 Hyperammonemia
Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy
and be told to inform the prescriber if any of these symptoms occur [see Warnings and
Precautions (5.8, 5.9)].
17.5 CNS Depression
Since valproate products may produce CNS depression, especially when combined with another
CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as
driving an automobile or operating dangerous machinery, until it is known that they do not
become drowsy from the drug.
17.6 Multi-Organ Hypersensitivity Reactions
Instruct patients that a fever associated with other organ system involvement (rash,
lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately
[see Warnings and Precautions (5.11)].
Manufactured at
Hospira, Inc.
McPherson, KS 67460 USA
Manufactured by
Hospira, Inc.
Lake Forest, IL 60045 USA
For
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
AbbVie Inc.
North Chicago, IL 60064, U.S.A.
EN-3483 Month Year
Reference ID: 3520933
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:36.474036
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018081s060,018082s043,018723s052,019680s039,020593s030,021168s028lbl.pdf', 'application_number': 18082, 'submission_type': 'SUPPL ', 'submission_number': 43}
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11,157
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1
TOLECTIN DS
(tolmetin sodium)
Capsules
TOLECTIN 600
(tolmetin sodium)
Tablets
For Oral Administration
Cardiovascular Risk
•
NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk may
increase with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk (see WARNINGS).
•
TOLECTIN is contraindicated for the treatment of peri-operative pain in the
setting
of
coronary
artery
bypass
graft
(CABG)
surgery
(see
CONTRAINDICATIONS and WARNINGS).
Gastrointestinal Risk
•
NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or intestines,
which can be fatal. These events can occur at any time during use and without
warning symptoms. Elderly patients are at greater risk for serious
gastrointestinal events (see WARNINGS).
DESCRIPTION
TOLECTIN DS (tolmetin sodium) capsules for oral administration contain tolmetin
sodium as the dihydrate in an amount equivalent to 400 mg of tolmetin. Each capsule
contains 36 mg (1.568 mEq) of sodium and the following inactive ingredients:
gelatin, magnesium stearate, corn starch, talc, FD&C Red No. 3, FD&C Yellow No.
6 and titanium dioxide.
TOLECTIN 600 (tolmetin sodium) tablets for oral administration contain tolmetin
sodium as the dihydrate in an amount equivalent to 600 mg of tolmetin. Each tablet
contains 54 mg (2.35 mEq) of sodium and the following inactive ingredients:
cellulose, silicon dioxide, crospovidone, hydroxypropyl methyl cellulose, magnesium
stearate, polyethylene glycol, corn starch, titanium dioxide, FD&C Yellow No. 6 and
D&C Yellow No. 10.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
The pKa of tolmetin is 3.5 and tolmetin sodium is freely soluble in water.
Tolmetin sodium is a nonselective nonsteroidal anti-inflammatory agent. The
structural formula is:
Sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate.
CLINICAL PHARMACOLOGY
Studies in animals have shown TOLECTIN (tolmetin sodium) to possess
anti-inflammatory, analgesic, and antipyretic activity. In the rat, TOLECTIN prevents
the development of experimentally induced polyarthritis and also decreases
established inflammation.
The mode of action for TOLECTIN is not known. However, studies in laboratory
animals and man have demonstrated that the anti-inflammatory action of TOLECTIN
is not due to pituitary-adrenal stimulation. TOLECTIN inhibits prostaglandin
synthetase in vitro and lowers the plasma level of prostaglandin E in man. This
reduction in prostaglandin synthesis may be responsible for the anti-inflammatory
action. TOLECTIN does not appear to alter the course of the underlying disease in
man.
In patients with rheumatoid arthritis and in normal volunteers, tolmetin sodium is
rapidly and almost completely absorbed with peak plasma levels being reached within
30-60 minutes after an oral therapeutic dose. In controlled studies, the time to reach
peak tolmetin plasma concentration is approximately 20 minutes longer following
administration of a 600 mg tablet, compared to an equivalent dose given as 200 mg
tablets. The clinical meaningfulness of this finding, if any, is unknown. Tolmetin
displays a biphasic elimination from the plasma consisting of a rapid phase with a
half-life of 1 to 2 hours followed by a slower phase with a half-life of about 5 hours.
Peak plasma levels of approximately 40 µg/mL are obtained with a 400 mg oral dose.
Essentially all of the administered dose is recovered in the urine in 24 hours either as
an inactive oxidative metabolite or as conjugates of tolmetin. An 18-day multiple
This label may not be the latest approved by FDA.
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3
dose study demonstrated no accumulation of tolmetin when compared with a single
dose.
In two fecal blood loss studies of 4 to 6 days duration involving 15 subjects each,
TOLECTIN did not induce an increase in blood loss over that observed during a
4-day drug-free control period. In the same studies, aspirin produced a greater blood
loss than occurred during the drug-free control period, and a greater blood loss than
occurred during the TOLECTIN treatment period. In one of the two studies,
indomethacin produced a greater fecal blood loss than occurred during the drug-free
control period; in the second study, indomethacin did not induce a significant increase
in blood loss.
TOLECTIN is effective in treating both the acute flares and in the long-term
management of the symptoms of rheumatoid arthritis, osteoarthritis and juvenile
rheumatoid arthritis.
In patients with either rheumatoid arthritis or osteoarthritis, TOLECTIN is as
effective as aspirin and indomethacin in controlling disease activity, but the frequency
of the milder gastrointestinal adverse effects and tinnitus was less than in
aspirin-treated patients, and the incidence of central nervous system adverse effects
was less than in indomethacin-treated patients.
In patients with juvenile rheumatoid arthritis, TOLECTIN is as effective as aspirin in
controlling disease activity, with a similar incidence of adverse reactions. Mean
SGOT values, initially elevated in patients on previous aspirin therapy, remained
elevated in the aspirin group and decreased in the TOLECTIN group.
TOLECTIN has produced additional therapeutic benefit when added to a regimen of
gold salts and, to a lesser extent, with corticosteroids. TOLECTIN should not be used
in conjunction with salicylates since greater benefit from the combination is not
likely, but the potential for adverse reactions is increased.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of TOLECTIN and other treatment
options before deciding to use TOLECTIN. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (see
WARNINGS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
TOLECTIN (tolmetin sodium) is indicated for the relief of signs and symptoms of
rheumatoid arthritis and osteoarthritis. TOLECTIN is indicated in the treatment of
acute flares and the long-term management of the chronic disease.
TOLECTIN is also indicated for treatment of juvenile rheumatoid arthritis. The safety
and effectiveness of TOLECTIN have not been established in pediatric patients under
2 years of age (see PRECAUTIONS: Pediatric Use and DOSAGE AND
ADMINSTRATION).
CONTRAINDICATIONS
TOLECTIN is contraindicated in patients with known hypersensitivity to tolmetin
sodium.
TOLECTIN should not be given to patients who have experienced asthma, urticaria
or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal,
anaphylactic-like reactions to NSAIDs have been reported in such patients (see
WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting
Asthma).
TOLECTIN is contraindicated for the treatment of peri-operative pain in the setting
of coronary artery bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
Cardiovascular Effects
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDS of up to three
years duration have shown an increased risk of serious cardiovascular (CV)
thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs,
both COX-2 selective and nonselective, may have a similar risk. Patients with known
CV disease or risk factors for CV disease may be at greater risk. To minimize the
potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and
patients should remain alert for the development of such events, even in the absence
of previous CV symptoms. Patients should be informed about the signs and/or
symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased
risk of serious CV thrombotic events associated with NSAID use. The concurrent use
of aspirin and an NSAID does increase the risk of serious GI events (see
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5
WARNINGS: Gastrointestinal (GI) Effects—Risk of Ulceration, Bleeding, and
Perforation).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of
pain in the first 10 to 14 days following CABG surgery found an increased incidence
of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including TOLECTIN, can lead to onset of new hypertension or worsening
of preexisting hypertension, either of which may contribute to the increased incidence
of CV events. Patients taking thiazides or loop diuretics may have impaired response
to these therapies when taking NSAIDs. NSAIDs, including TOLECTIN, should be
used with caution in patients with hypertension. Blood pressure (BP) should be
monitored closely during the initiation of NSAID treatment and throughout the course
of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs.
TOLECTIN should be used with caution in patients with fluid retention or heart
failure.
Gastrointestinal (GI) Effects—Risk of Ulceration, Bleeding, and
Perforation
NSAIDs, including TOLECTIN, can cause serious gastrointestinal adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach, small
intestine or large intestine, which can be fatal. These serious adverse events can occur
at any time, with or without warning symptoms in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by
NSAIDS occur in approximately 1% of patients treated for 3 to 6 months, and in
about 2 to 4% of patients treated for one year. These trends continue with longer
duration of use, increasing the likelihood of developing a serious GI event at some
time during the course of therapy. However, even short-term therapy is not without
risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of
ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer
disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold
increased risk for developing a GI bleed compared to patients with neither of these
risk factors. Other factors that increase the risk for GI bleeding in patients treated
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
with NSAIDs include concomitant use of oral corticosteroids or anticoagulants,
longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and, therefore, special care should be taken in treating this
population.
To minimize the potential risk for an adverse GI event in patients treated with an
NSAID, the lowest effective dose should be used for the shortest possible duration.
Patients and physicians should remain alert for signs and symptoms of GI ulceration
and bleeding during NSAID therapy and promptly initiate additional evaluation and
treatment if a serious GI adverse event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-
risk patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and
other renal injury. Acute interstitial nephritis with hematuria, proteinuria, and
occasionally nephritic syndrome have been reported in patients treated with
TOLECTIN. Renal toxicity has also been seen in patients in whom renal
prostaglandins have a compensatory role in the maintenance of renal perfusion. In
these patients, administration of an NSAID may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which may precipitate
overt renal decompensation. Patients at greatest risk of this reaction are those with
impaired renal function, heart failure, liver dysfunction, those taking diuretics and
ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually
followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical trials regarding the use of
TOLECTIN in patients with advanced renal disease. Therefore, treatment with
TOLECTIN is not recommended in these patients with advanced renal disease. If
TOLECTIN therapy must be initiated, close monitoring of the patient’s renal function
is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients with known
prior exposure to TOLECTIN. TOLECTIN should not be given to patients with the
aspirin triad. This symptom complex typically occurs in asthmatic patients who
experience rhinitis with or without nasal polyps, or who exhibit severe, potentially
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
fatal
bronchospasm
after
taking
aspirin
or
other
NSAIDS
(see
CONTRAINDICATIONS
and
PRECAUTIONS:
Preexisting
Asthma).
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including TOLECTIN, can cause serious skin adverse events such as
exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal
necrolysis (TEN), which can be fatal. These serious events may occur without
warning. Patients should be informed about the signs and symptoms of serious skin
manifestations and use of the drug should be discontinued at the first appearance of
skin rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, TOLECTIN should be avoided because it
may cause premature closure of the ductus arteriosus (see also PRECAUTIONS:
Pregnancy).
PRECAUTIONS
General
TOLECTIN cannot be expected to substitute for corticosteroids or to treat
corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to
disease exacerbation. Patients on prolonged corticosteroid therapy should have their
therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of TOLECTIN in reducing fever and inflammation may
diminish the utility of these diagnostic signs in detecting complications of presumed
noninfectious, painful conditions.
Ophthalmological Effects
Because of ocular changes observed in animals and of reports of adverse eye findings
with NSAIDs, it is recommended that patients who develop visual disturbances
during treatment with TOLECTIN have ophthalmologic evaluations.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients
taking NSAIDs, including TOLECTIN. These laboratory abnormalities may progress,
may remain unchanged, or may be transient with continuing therapy. Notable
elevations of ALT or AST (approximately three or more times the upper limit of
normal) have been reported in approximately 1% of patients in clinical trials with
NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal
outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an
abnormal liver test has occurred should be evaluated for evidence of the development
of a more severe hepatic reaction while on therapy with TOLECTIN. If clinical signs
and symptoms consistent with liver disease develop, or if systemic manifestations
occur (e.g., eosinophilia, rash, etc.), TOLECTIN should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including TOLECTIN. This
may be due to fluid retention, occult or gross GI blood loss, or an incompletely
described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs,
including TOLECTIN, should have their hemoglobin or hematocrit checked if they
exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and
have been shown to prolong bleeding time in some patients. Unlike aspirin, their
effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving TOLECTIN who may be adversely affected by alterations in
platelet function, such as those with coagulation disorders or patients receiving
anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients
with aspirin-sensitive asthma has been associated with severe bronchospasm which
can be fatal. Since cross reactivity, including bronchospasm, between aspirin and
other NSAIDs has been reported in such aspirin-sensitive patients, TOLECTIN
should not be administered to patients with this form of aspirin sensitivity and should
be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing therapy.
Patients should also be encouraged to read the NSAID Medication Guide that
accompanies each prescription dispensed.
1. TOLECTIN, like other NSAIDs, may cause serious CV side effects, such as
MI or stroke, which may result in hospitalization and even death. Although
serious CV events can occur without warning symptoms, patients should be
alert for the signs and symptoms of chest pain, shortness of breath, weakness,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
slurring of speech, and should ask for medical advice when observing any
indicative signs or symptoms. Patients should be apprised of the importance of
this follow-up (see WARNINGS: Cardiovascular Effects).
2. TOLECTIN, like other NSAIDs, can cause GI discomfort and, rarely, serious
GI side effects, such as ulcers and bleeding, which may result in
hospitalization and even death. Although serious GI tract ulcerations and
bleeding can occur without warning symptoms, patients should be alert for the
signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative signs or symptoms including epigastric
pain, dyspepsia, melena, and hematemesis Patients should be apprised of the
importance of this follow-up (see WARNINGS: Gastrointestinal (GI)
Effects—Risk of Ulceration, Bleeding, and Perforation).
3. TOLECTIN, like other NSAIDs, can cause serious skin side effects such as
exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and
even death. Although serious skin reactions may occur without warning,
patients should be alert for the signs and symptoms of skin rash and blisters,
fever, or other signs of hypersensitivity, such as itching, and should ask for
medical advise when observing any indicative signs or symptoms. Patients
should be advised to stop the drug immediately if they develop any type of
rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight
gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper
quadrant tenderness, and “flu-like” symptoms). If these occur, patients should
be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g.,
difficulty breathing, swelling of the face or throat). If these occur, patients
should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, TOLECTIN should be avoided
because it will cause premature closure of the ductus arteriosus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning
symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients
on long-term treatment with NSAIDs should have their CBC and a chemistry profile
checked periodically. If clinical signs and symptoms consistent with liver or renal
disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if
abnormal liver tests persist or worsen, TOLECTIN should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs
concomitantly with ACE-inhibitors.
Aspirin
As with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is
not generally recommended because of the potential of increased adverse effects.
Diuretics
Clinical studies, as well as post-marketing observations, have shown that NSAIDs
can reduce the natriuretic effect of furosemide and thiazides in some patients. This
response has been attributed to inhibition of renal prostaglandin synthesis. During
concomitant therapy with NSAIDs, the patient should be observed closely for signs of
renal failure, as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal
lithium clearance. The mean minimum lithium concentration increased 15% and the
renal clearance was decreased by approximately 20%. These effects have been
attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when
NSAIDs and lithium are administered concurrently, subjects should be observed
carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of
methotrexate. Caution should be used when NSAIDs are administered concomitantly
with methotrexate.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of
both drugs together have a risk of serious GI bleeding higher than users of either drug
alone.
The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin,
and tolmetin does not alter the prothrombin time of normal volunteers. However,
increased prothrombin time and bleeding have been reported in patients on
concomitant TOLECTIN and warfarin therapy. Therefore, caution should be
exercised when administering TOLECTIN to patients on anticoagulants.
Hypoglycemic Agents
In adult diabetic patients under treatment with either sulfonylureas or insulin there is
no change in the clinical effects of either TOLECTIN or the hypoglycemic agents.
Drug/Laboratory Test Interactions
The metabolites of tolmetin sodium in urine have been found to give positive tests for
proteinuria using tests which rely on acid precipitation as their endpoint
(e.g., sulfosalicylic acid). No interference is seen in the tests for proteinuria using
dye-impregnated commercially available reagent strips (e.g., Albustix®, Uristix®,
etc.).
Drug-Food Interactions
In a controlled single-dose study, administration of TOLECTIN with milk had no
effect on peak plasma tolmetin concentrations, but decreased total tolmetin
bioavailability by 16%. When TOLECTIN was taken immediately after a meal, peak
plasma tolmetin concentrations were reduced by 50% while total bioavailability was
again decreased by 16%.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tolmetin sodium did not possess any carcinogenic liability in the following long-term
studies: a 24-month study in rats at doses as high as 75 mg/kg/day, and an 18-month
study in mice at doses as high as 50 mg/kg/day.
No mutagenic potential of tolmetin sodium was found in the Ames
Salmonella-Microsomal Activation Test.
Reproductive studies revealed no impairment of fertility in animals. Effects on
parturition have been shown, however, as with other prostaglandin inhibitors. This
information is detailed in the Pregnancy section.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Pregnancy
Teratogenic Effects: Pregnancy Category C
Reproduction studies in rats and rabbits at doses up to 50 mg/kg (1.5 times the
maximum clinical dose based on a body weight of 60 kg) revealed no evidence of
teratogenesis or impaired fertility due to TOLECTIN. However, animal reproduction
studies are not always predictive of human response. There are no adequate and well-
controlled studies in pregnant women. TOLECTIN should be used in pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of NSAIDs on the fetal cardiovascular system (closure
of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin
synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup
survival occurred. The effects of TOLECTIN on labor and delivery in pregnant
women are unknown.
Nursing Mothers
Tolmetin sodium has been shown to be secreted in human milk. Because of the
potential for serious adverse reactions in nursing infants from tolmetin sodium, a
decision should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 years have not been
established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years
and older).
ADVERSE REACTIONS
The adverse reactions which have been observed in clinical trials encompass
observations in about 4370 patients treated with TOLECTIN (tolmetin sodium), over
800 of whom have undergone at least one year of therapy. These adverse reactions,
reported below by body system, are among those typical of nonsteroidal
anti-inflammatory drugs and, as expected, gastrointestinal complaints were most
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
frequent. In clinical trials with TOLECTIN, about 10% of patients dropped out
because of adverse reactions, mostly gastrointestinal in nature.
Incidence Greater Than 1%
The following adverse reactions which occurred more frequently than 1 in 100 were
reported in controlled clinical trials.
Gastrointestinal: Nausea (11%), dyspepsia,* gastrointestinal distress,* abdominal
pain,* diarrhea,* flatulence,* vomiting,* constipation, gastritis, and peptic ulcer.
Forty percent of the ulcer patients had a prior history of peptic ulcer disease and/or
were receiving concomitant anti-inflammatory drugs including corticosteroids, which
are known to produce peptic ulceration.
Body as a Whole: Headache, * asthenia, * chest pain
Cardiovascular: Elevated blood pressure, * edema*
Central Nervous System: Dizziness, * drowsiness, depression
Metabolic/Nutritional: Weight gain, * weight loss*
Dermatologic: Skin irritation
Special Senses: Tinnitus, visual disturbance
Hematologic: Small and transient decreases in hemoglobin and hematocrit not
associated with gastrointestinal bleeding have occurred. These are similar to changes
reported with other nonsteroidal anti-inflammatory drugs.
Urogenital: Elevated BUN, urinary tract infection
*Reactions occurring in 3% to 9% of patients treated with TOLECTIN. Reactions
occurring in fewer than 3% of the patients are unmarked.
Incidence Less Than 1%
(Causal Relationship Probable)
The following adverse reactions were reported less frequently than 1 in
100 controlled clinical trials or were reported since marketing. The probability exists
that there is a causal relationship between TOLECTIN and these adverse reactions.
Gastrointestinal: Gastrointestinal bleeding with or without evidence of peptic ulcer,
perforation, glossitis, stomatitis, hepatitis, liver function abnormalities.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Body as a Whole: Anaphylactoid reactions, fever, lymphadenopathy, serum sickness
Hematologic:
Hemolytic
anemia,
thrombocytopenia,
granulocytopenia,
agranulocytosis
Cardiovascular: Congestive heart failure in patients with marginal cardiac function.
Dermatologic: Urticaria, purpura, erythema multiforme, toxic epidermal necrolysis
Urogenital: Hematuria, proteinuria, dysuria, renal failure
Incidence Less Than 1%
(Causal Relationship Unknown)
Other adverse reactions were reported less frequently than 1 in 100 in controlled
clinical trials or were reported since marketing, but a causal relationship between
TOLECTIN and the reaction could not be determined. These rarely reported reactions
are being listed as alerting information for the physician since the possibility of a
causal relationship cannot be excluded.
Body as a Whole: Epistaxis
Special Senses: Optic neuropathy, retinal and macular changes
MANAGEMENT OF OVERDOSAGE
In the event of overdosage, the stomach should be emptied by inducing vomiting or
by gastric lavage followed by the administration of activated charcoal.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of TOLECTIN and other treatment
options before deciding to use TOLECTIN. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (see
WARNINGS).
After observing the response to initial therapy with TOLECTIN, the dose and
frequency should be adjusted to suit an individual patient’s needs.
For the relief of rheumatoid arthritis or osteoarthritis, the recommended starting dose
for adults is 400 mg three times daily (1200 mg daily), preferably including a dose on
arising and a dose at bedtime. To achieve optimal therapeutic effect the dose should
be adjusted according to the patient’s response after one or two weeks. Control is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
usually achieved at doses of 600-1800 mg daily in divided doses (generally t.i.d.).
Doses larger than 1800 mg/day have not been studied and are not recommended.
For the relief of juvenile rheumatoid arthritis, the recommended starting dose for
pediatric patients (2 years and older) is 20 mg/kg/day in divided doses (t.i.d. or q.i.d.).
When control has been achieved, the usual dose ranges from 15 to 30 mg/kg/day.
Doses higher than 30 mg/kg/day have not been studied, and, therefore, are not
recommended.
A therapeutic response to TOLECTIN (tolmetin sodium) can be expected in a few
days to a week. Progressive improvement can be anticipated during succeeding weeks
of therapy. If gastrointestinal symptoms occur, TOLECTIN can be administered with
antacids
other
than
sodium
bicarbonate.
TOLECTIN
bioavailability
and
pharmacokinetics are not significantly affected by acute or chronic administration of
magnesium and aluminum hydroxides; however, bioavailability is affected by food or
milk (see PRECAUTIONS: Drug-Food Interaction).
HOW SUPPLIED
TOLECTIN DS (tolmetin sodium) capsules 400 mg (colored orange opaque with
contrasting parallel bands, imprinted “TOLECTIN DS” and “McNEIL”), NDC
0045-0414, bottles of 100 and 500.
TOLECTIN® 600 (tolmetin sodium) tablets 600 mg (colored orange, film coated,
imprinted “TOLECTIN 600” and “McNEIL”), NDC 0045-0416, bottles of 100 and
500.
Dispense in tight, light-resistant container as defined in the official compendium.
Store at controlled room temperature (15°-30°C, 59°-86°F). Protect from light.
ORTHO-McNEIL logo
OMP DIVISION
ORTHO-McNEIL PHARMACEUTICAL, INC.
Raritan, NJ 08869
Printed in U.S.A.
©OMP 2006
Revised February 2006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that
can lead to death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery
called a “coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and
intestines at any time during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation)
from medical conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any
other NSAID medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can
interact with each other and cause serious side effects. Keep a list of your
medicines to show your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women
late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling
(fluid retention)
• kidney problems including kidney
failure
• bleeding and ulcers in the stomach
and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver
failure
• asthma attacks in people who have
asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Stop your NSAID medicine and call your healthcare provider right away if you have
any of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands, and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider
or pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart
attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin
can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription
(over-the-counter). Talk to your healthcare provider before using over-the-counter
NSAIDs for more than 10 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with
hydrocodone), Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketroprofen
Orovail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan,
Naprapac (copackaged with Iansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
*Vicoprofen contains the same dose of ibuprofen as over-the-counter NSAIDs, and is usually used for less
than 10 days to treat pain. The OTC NSAID label warns that long-term continuous use may increase the
risk of heart attack or stroke.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
August 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:36.527933
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018084s052,017628s068lbl.pdf', 'application_number': 18084, 'submission_type': 'SUPPL ', 'submission_number': 52}
|
11,158
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9010842
1
STERILE OPHTHALMIC SOLUTION
TIMOPTIC®
0.25% AND 0.5%
(TIMOLOL MALEATE
OPHTHALMIC SOLUTION)
DESCRIPTION
TIMOPTIC* (timolol maleate ophthalmic solution) is a non-selective beta-adrenergic receptor blocking
agent. Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol
maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is
provided as the levo-isomer. The optical rotation of timolol maleate is:
25°
[α]
in 1.0N HCl (C = 5%) = –12.2° (–11.7° to –12.5°).
405 nm
Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is:
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is
soluble in water, methanol, and alcohol. TIMOPTIC is stable at room temperature.
TIMOPTIC Ophthalmic Solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol
maleate in two dosage strengths: Each mL of TIMOPTIC 0.25% contains 2.5 mg of timolol (3.4 mg of
timolol maleate). Each mL of TIMOPTIC 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate).
Inactive ingredients: monobasic and dibasic sodium phosphate, sodium hydroxide to adjust pH, and water
for injection. Benzalkonium chloride 0.01% is added as preservative.
CLINICAL PHARMACOLOGY
Mechanism of Action
Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not
have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-
stabilizing) activity.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with
heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor
blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain
adequate cardiac function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway
resistance from unopposed parasympathetic activity. Such an effect in patients with asthma or other
bronchospastic conditions is potentially dangerous.
TIMOPTIC Ophthalmic Solution, when applied topically on the eye, has the action of reducing elevated
as well as normal intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular
pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level
of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve
damage.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1985, 1995
All rights reserved
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TIMOPTIC® (timolol maleate ophthalmic solution)
9010842
2
The onset of reduction in intraocular pressure following administration of TIMOPTIC can usually be
detected within one-half hour after a single dose. The maximum effect usually occurs in one to two hours
and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours with a
single dose. Repeated observations over a period of one year indicate that the intraocular pressure-
lowering effect of TIMOPTIC is well maintained.
The precise mechanism of the ocular hypotensive action of TIMOPTIC is not clearly established at this
time. Tonography and fluorophotometry studies in man suggest that its predominant action may be related
to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also
observed.
Pharmacokinetics
In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was
determined following twice daily administration of TIMOPTIC 0.5%. The mean peak plasma concentration
following morning dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL.
Clinical Studies
In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater,
TIMOPTIC 0.25 percent or 0.5 percent administered twice a day produced a greater reduction in
intraocular pressure than 1, 2, 3, or 4 percent pilocarpine solution administered four times a day or 0.5, 1,
or 2 percent epinephrine hydrochloride solution administered twice a day.
In these studies, TIMOPTIC was generally well tolerated and produced fewer and less severe side
effects than either pilocarpine or epinephrine. A slight reduction of resting heart rate in some patients
receiving TIMOPTIC (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.
INDICATIONS AND USAGE
TIMOPTIC Ophthalmic Solution is indicated in the treatment of elevated intraocular pressure in
patients with ocular hypertension or open-angle glaucoma.
CONTRAINDICATIONS
TIMOPTIC is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma;
(3) severe chronic obstructive pulmonary disease (see WARNINGS); (4) sinus bradycardia; (5) second or
third degree atrioventricular block; (6) overt cardiac failure (see WARNINGS); (7) cardiogenic shock; or
(8) hypersensitivity to any component of this product.
WARNINGS
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
The same adverse reactions found with systemic administration of beta-adrenergic blocking
agents may occur with topical administration. For example, severe respiratory reactions and
cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death
in association with cardiac failure, have been reported following systemic or ophthalmic
administration of timolol maleate (see CONTRAINDICATIONS).
Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished
myocardial contractility, and its inhibition of beta-adrenergic receptor blockade may precipitate more
severe failure.
In Patients Without a History of Cardiac Failure continued depression of the myocardium with beta-
blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or
symptom of cardiac failure, TIMOPTIC should be discontinued.
Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or
moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial
asthma
or
a
history
of
bronchial
asthma,
in
which
TIMOPTIC
is
contraindicated
[see
CONTRAINDICATIONS]) should, in general, not receive beta-blockers, including TIMOPTIC.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TIMOPTIC® (timolol maleate ophthalmic solution)
9010842
3
Major Surgery
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is
controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-
adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical
procedures. Some patients receiving beta-adrenergic receptor blocking agents have experienced
protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has
also been reported. For these reasons, in patients undergoing elective surgery, some authorities
recommend gradual withdrawal of beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by
sufficient doses of adrenergic agonists.
Diabetes Mellitus
Beta-adrenergic blocking agents should be administered with caution in patients subject to
spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving
insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and
symptoms of acute hypoglycemia.
Thyrotoxicosis
Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.
Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of
beta-adrenergic blocking agents that might precipitate a thyroid storm.
PRECAUTIONS
General
Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these
agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms
suggesting reduced cerebral blood flow develop following initiation of therapy with TIMOPTIC, alternative
therapy should be considered.
There have been reports of bacterial keratitis associated with the use of multiple dose containers of
topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in
most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. (See
PRECAUTIONS, Information for Patients.)
Choroidal detachment after filtration procedures has been reported with the administration of aqueous
suppressant therapy (e.g. timolol).
Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment
is to reopen the angle. This requires constricting the pupil. Timolol maleate has little or no effect on the
pupil. TIMOPTIC should not be used alone in the treatment of angle-closure glaucoma.
Anaphylaxis: While taking beta-blockers, patients with a history of atopy or a history of severe
anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or
therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of
epinephrine used to treat anaphylactic reactions.
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness
consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol
has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or
myasthenic symptoms.
Information for Patients
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or
surrounding structures.
Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the
dispensing container contacts the eye or surrounding structures, can become contaminated by common
bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may
result from using contaminated solutions. (See PRECAUTIONS, General.)
Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular
condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the
continued use of the present multidose container.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TIMOPTIC® (timolol maleate ophthalmic solution)
9010842
4
Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary
disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be
advised not to take this product. (See CONTRAINDICATIONS.)
Patients should be advised that TIMOPTIC contains benzalkonium chloride which may be absorbed by
soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may
be reinserted 15 minutes following TIMOPTIC administration.
Drug Interactions
Although TIMOPTIC used alone has little or no effect on pupil size, mydriasis resulting from
concomitant therapy with TIMOPTIC and epinephrine has been reported occasionally.
Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally
and TIMOPTIC should be observed for potential additive effects of beta-blockade, both systemic and on
intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not
recommended.
Calcium antagonists: Caution should be used in the coadministration of beta-adrenergic blocking
agents, such as TIMOPTIC, and oral or intravenous calcium antagonists because of possible
atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired
cardiac function, coadministration should be avoided.
Catecholamine-depleting drugs: Close observation of the patient is recommended when a beta blocker
is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of
possible additive effects and the production of hypotension and/or marked bradycardia, which may result
in vertigo, syncope, or postural hypotension.
Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with
digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.
Quinidine: Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during
combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of
timolol via the P-450 enzyme, CYP2D6.
Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can
follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension
with ophthalmic timolol maleate.
Injectable epinephrine: (See PRECAUTIONS, General, Anaphylaxis)
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year study of timolol maleate administered orally to rats, there was a statistically significant
increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day
(approximately 42,000 times the systemic exposure following the maximum recommended human
ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to
approximately 14,000 times the maximum recommended human ophthalmic dose.
In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign
and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice
at 500 mg/kg/day, (approximately 71,000 times the systemic exposure following the maximum
recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000,
respectively, times the systemic exposure following the maximum recommended human ophthalmic
dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the
uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again
observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with elevations in serum
prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5
or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated
with administration of several other therapeutic agents that elevate serum prolactin, but no correlation
between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in
adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum
recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.
Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus
test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay
(up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TIMOPTIC® (timolol maleate ophthalmic solution)
9010842
5
mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain
TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain
TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants
did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.
Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at
doses up to 21,000 times the systemic exposure following the maximum recommended human
ophthalmic dose.
Pregnancy:
Teratogenic Effects — Pregnancy Category C. Teratogenicity studies with timolol in mice, rats, and
rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum
recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although
delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal
development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the
maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an
increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of
14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in
this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in pregnant women. TIMOPTIC should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Timolol maleate has been detected in human milk following oral and ophthalmic drug administration.
Because of the potential for serious adverse reactions from TIMOPTIC in nursing infants, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and younger
patients.
ADVERSE REACTIONS
The most frequently reported adverse experiences have been burning and stinging upon instillation
(approximately one in eight patients).
The following additional adverse experiences have been reported less frequently with ocular
administration of this or other timolol maleate formulations:
BODY AS A WHOLE
Headache, asthenia/fatigue, and chest pain.
CARDIOVASCULAR
Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident,
cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary
edema, edema, claudication, Raynaud’s phenomenon, and cold hands and feet.
DIGESTIVE
Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.
IMMUNOLOGIC
Systemic lupus erythematosus.
NERVOUS SYSTEM/PSYCHIATRIC
Dizziness, increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia,
nightmares, behavioral changes and psychic disturbances including depression, confusion, hallucinations,
anxiety, disorientation, nervousness, and memory loss.
SKIN
Alopecia and psoriasiform rash or exacerbation of psoriasis.
HYPERSENSITIVITY
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TIMOPTIC® (timolol maleate ophthalmic solution)
9010842
6
Signs and symptoms of systemic allergic reactions, including angioedema, urticaria, and localized and
generalized rash.
RESPIRATORY
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure,
dyspnea, nasal congestion, cough and upper respiratory infections.
ENDOCRINE
Masked symptoms of hypoglycemia in diabetic patients (see WARNINGS).
SPECIAL SENSES
Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain,
discharge (e.g., crusting), foreign body sensation, itching and tearing, and dry eyes; ptosis; decreased
corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia;
pseudopemphigoid; choroidal detachment following filtration surgery (see PRECAUTIONS, General); and
tinnitus.
UROGENITAL
Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie’s disease.
The following additional adverse effects have been reported in clinical experience with ORAL timolol
maleate or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic
timolol maleate: Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm
with respiratory distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss;
Cardiovascular: Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain,
hepatomegaly,
vomiting,
mesenteric
arterial
thrombosis,
ischemic
colitis;
Hematologic:
Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulocytosis; Endocrine: Hyperglycemia,
hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating; Musculoskeletal: Arthralgia;
Nervous System/Psychiatric: Vertigo, local weakness, diminished concentration, reversible mental
depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time
and place, emotional lability,
slightly
clouded
sensorium,
and
decreased
performance
on
neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties.
OVERDOSAGE
There have been reports of inadvertent overdosage with TIMOPTIC Ophthalmic Solution resulting in
systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness,
headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see also ADVERSE
REACTIONS).
Overdosage has been reported with Tablets BLOCADREN* (timolol maleate tablets). A 30 year old
female ingested 650 mg of BLOCADREN (maximum recommended oral daily dose is 60 mg) and
experienced second and third degree heart block. She recovered without treatment but approximately two
months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse
rate, and borderline first degree heart block.
An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that
timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that
timolol did not dialyze readily.
DOSAGE AND ADMINISTRATION
TIMOPTIC Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual
starting dose is one drop of 0.25 percent TIMOPTIC in the affected eye(s) twice a day. If the clinical
response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected
eye(s) twice a day.
Since in some patients the pressure-lowering response to TIMOPTIC may require a few weeks to
stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of
treatment with TIMOPTIC.
If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to
one drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TIMOPTIC® (timolol maleate ophthalmic solution)
9010842
7
satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure at
different times during the day.
Dosages above one drop of 0.5 percent TIMOPTIC twice a day generally have not been shown to
produce further reduction in intraocular pressure. If the patient’s intraocular pressure is still not at a
satisfactory level on this regimen, concomitant therapy with other agent(s) for lowering intraocular
pressure can be instituted. The concomitant use of two topical beta-adrenergic blocking agents is not
recommended. (See PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)
HOW SUPPLIED
Sterile Ophthalmic Solution TIMOPTIC is a clear, colorless to light yellow solution.
No. 8895 — TIMOPTIC Ophthalmic Solution, 0.25% timolol equivalent, is supplied in an
OCUMETER®* PLUS container, a white, opaque, plastic ophthalmic dispenser with a controlled drop tip as
follows:
NDC 0006-8895-35, 5 mL
NDC 0006-8895-36, 10 mL
No. 8896 — TIMOPTIC Ophthalmic Solution, 0.5% timolol equivalent, is supplied in an OCUMETER®
PLUS container, a white, opaque, plastic ophthalmic dispenser with a controlled drop tip as follows:
NDC 0006-8896-35, 5 mL
NDC 0006-8896-36, 10 mL
Storage
Store at room temperature, 15-30°C (59-86°F). Protect from freezing. Protect from light.
By: Laboratories Merck Sharp & Dohme-Chibret
63963 Clermont-Ferrand Cedex 9, France
Issued April 2000
XXXX-XX/XX XXXXXXX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
STERILE OPHTHALMIC SOLUTION
TIMOPTIC®
0.25% AND 0.5%
(TIMOLOL MALEATE
OPHTHALMIC SOLUTION)
XXXXXXX
8
INSTRUCTIONS FOR USE
Please follow these instructions carefully when using TIMOPTIC*. Use TIMOPTIC as prescribed by your
doctor.
1. If you use other topically applied ophthalmic medications, they should be administered at least 10
minutes before or after TIMOPTIC.
2. Wash hands before each use.
3. Before using the medication, be sure the Safety Strip on the front of the bottle is unbroken. A gap
between the bottle and the cap is normal for an unopened bottle.
4. Tear off the Safety Strip to break the seal.
5. To open the bottle, unscrew the cap by turning as indicated by the arrows.
Opening Arrows
Safety Strip
Gap
Finger Push Area
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For current labeling information, please visit https://www.fda.gov/drugsatfda
TIMOPTIC® (timolol maleate ophthalmic solution)
XXXXXXX
9
6. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and
your eye.
7. Invert the bottle, grasping it with the thumb or index finger over the Finger Push Area as shown.
Press lightly until a single drop is dispensed into the eye as directed by your doctor.
DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.
Ophthalmic medications, if handled improperly, can become contaminated by common bacteria
known to cause eye infections. Serious damage to the eye and subsequent loss of vision may result
from using contaminated ophthalmic medications. If you think your medication may be contaminated,
or if you develop an eye infection, contact your doctor immediately concerning continued use of this
bottle.
8. Repeat steps 6 & 7 with the other eye if instructed to do so by your doctor.
9. Replace the cap by turning until it is firmly touching the bottle.
10. The dispenser tip is designed to provide a pre-measured drop; therefore, do NOT enlarge the hole of
the dispenser.
WARNING: Keep out of reach of children.
If you have any questions about the use of TIMOPTIC, please consult your doctor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TIMOPTIC® (timolol maleate ophthalmic solution)
XXXXXXX
10
*Registered trademark of MERCK & CO., Inc.
MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., XXXX
West Point, PA 19486, USA
All rights reserved
Issued XXXX XXXX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:36.582943
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18086S54lbl.pdf', 'application_number': 18086, 'submission_type': 'SUPPL ', 'submission_number': 54}
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SYMMETREL®
(Amantadine Hydrochloride, USP)
Tablets and Syrup
Rx only
DESCRIPTION
SYMMETREL (Amantadine Hydrochloride, USP) is designated generically as amantadine
hydrochloride and chemically as 1-adamantanamine hydrochloride.
Amantadine hydrochloride is a stable white or nearly white crystalline powder, freely soluble in water
and soluble in alcohol and in chloroform.
Amantadine hydrochloride has pharmacological actions as both an anti-Parkinson and an antiviral
drug.
SYMMETREL is available in tablets and syrup.
Each tablet intended for oral administration contains 100 mg amantadine hydrochloride and has the
following inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline
cellulose, sodium starch glycolate, FD&C Yellow No. 6.
SYMMETREL syrup contains 50 mg of amantadine hydrochloride per 5 mL and has the following
inactive ingredients: artificial raspberry flavor, citric acid, methylparaben, propylparaben, and sorbitol
solution.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Mechanism of Action: Antiviral
The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to
mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the
function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also
known to prevent virus assembly during virus replication. It does not appear to interfere with the
immunogenicity of inactivated influenza A virus vaccine.
• HCl
NH2
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NDA 18-101/S-014
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Antiviral Activity
Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1,
H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative
relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical
response to therapy has not been established in man. Sensitivity test results, expressed as the
concentration of amantadine required to inhibit by 50% the growth of virus (ED50) in tissue culture
vary greatly (from 0.1 µg/mL to 25.0 µg/mL) depending upon the assay protocol used, size of virus
inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture
readily tolerated amantadine up to a concentration of
100 µg/mL.
Drug Resistance
Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic
strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro
sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative
relationship between the in vitro sensitivity of influenza A variants to amantadine and the clinical
response to therapy has not been established.
Mechanism of Action: Parkinson’s Disease
The mechanism of action of amantadine in the treatment of Parkinson’s disease and drug-induced
extrapyramidal reactions is not known. Data from earlier animal studies suggest that SYMMETREL
may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that
amantadine is a weak, non-competitive NMDA receptor antagonist (Ki = 10µM). Although amantadine
has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits
anticholinergic-like side effects such as dry mouth, urinary retention, and constipation.
Pharmacokinetics
SYMMETREL is well absorbed orally. Maximum plasma concentrations are directly related to dose
for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase
in maximum plasma concentrations. It is primarily excreted unchanged in the urine by glomerular
filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine.
One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5-15%
of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent
amantadine plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg
dose of amantadine. Acetylamantadine was not detected in the plasma of the remaining seven
volunteers. The contribution of this metabolite to efficacy or toxicity is not known.
There appears to be a relationship between plasma amantadine concentrations and toxicity. As
concentration increases, toxicity seems to be more prevalent, however, absolute values of amantadine
concentrations associated with adverse effects have not been fully defined.
Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral
administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD
maximum plasma concentration was 0.22 ± 0.03 µg/mL (range: 0.18 to 0.32 µg/mL). The time to peak
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NDA 16-023/S-039
NDA 18-101/S-014
Page 5
concentration was 3.3 ± 1.5 hours (range: 1.5 to 8.0 hours). The apparent oral clearance was 0.28 ±
0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25 hours).
Across other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to 31 hours) in
19 healthy volunteers.
After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers, the
mean ± SD maximum plasma concentration Cmax was 0.24 ± 0.04 µg/mL and ranged from 0.18 to 0.28
µg/mL. After 15 days of amantadine 100 mg b.i.d., the Cmax was 0.47 ± 0.11 µg/mL in four of the five
volunteers. The administration of amantadine tablets as a 200 mg single dose to 6 healthy subjects
resulted in a Cmax of 0.51 ± 0.14 µg/mL. Across studies, the time to Cmax (Tmax) averaged about 2 to 4
hours.
Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg
intravenous doses of amantadine to 15 healthy volunteers.
In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma clearance was
0.79 ± 0.17 (mean ± SD).
The volume of distribution determined after the intravenous administration of amantadine to 15
healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg
doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal mucus at
mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 µg/g at 1, 4, and 8 hours after
dosing, respectively. These concentrations represented 31 ± 33%, 59 ± 61%, and 95 ± 86% of the
corresponding plasma amantadine concentrations. Amantadine is approximately 67% bound to plasma
proteins over a concentration range of 0.1 to 2.0 µg/mL. Following the administration of amantadine
100 mg as a single dose, the mean ± SD red blood cell to plasma ratio ranged from 2.7 ± 0.5 in 6
healthy subjects to 1.4 ± 0.2 in 8 patients with renal insufficiency.
The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma
concentrations are increased in healthy elderly individuals age 60 and older. After single dose
administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma clearance of
amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life was 29 ± 7 hours
(range 20 to 41 hours). Whether these changes are due to decline in renal function or other age related
factors is not known.
In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for body
mass index, was 1.5 fold higher in males compared to females (p<0.032).
Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly
reduced in adult patients with renal insufficiency. The elimination half-life increases two to three fold
or greater when creatinine clearance is less than 40 mL/min/1.73 m2 and averages eight days in
patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts by
hemodialysis.
The pH of the urine has been reported to influence the excretion rate of SYMMETREL. Since the
excretion rate of SYMMETREL increases rapidly when the urine is acidic, the administration of urine
acidifying drugs may increase the elimination of the drug from the body.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-023/S-039
NDA 18-101/S-014
Page 6
INDICATIONS AND USAGE
SYMMETREL is indicated for the prophylaxis and treatment of signs and symptoms of infection
caused by various strains of influenza A virus. SYMMETREL is also indicated in the treatment of
parkinsonism and drug-induced extrapyramidal reactions.
Influenza A Prophylaxis
SYMMETREL (Amantadine Hydrochloride, USP) is indicated for chemoprophylaxis against signs and
symptoms of influenza A virus infection when early vaccination is not feasible or when the vaccine is
contraindicated or not available. In the prophylaxis of influenza, early vaccination on an annual basis
as recommended by the Centers for Disease Control’s Immunization Practices Advisory Committee is
the method of choice. Because SYMMETREL does not completely prevent the host immune response
to influenza A infection, individuals who take this drug may still develop immune responses to natural
disease or vaccination and may be protected when later exposed to antigenically related viruses.
Following vaccination during an influenza A outbreak, SYMMETREL prophylaxis should be
considered for the 2- to 4-week time period required to develop an antibody response.
Influenza A Treatment
SYMMETREL is also indicated in the treatment of uncomplicated respiratory tract illness caused by
influenza A virus strains especially when administered early in the course of illness. There are no well-
controlled clinical studies demonstrating that treatment with SYMMETREL will avoid the
development of influenza A virus pneumonitis or other complications in high risk patients.
There is no clinical evidence indicating that SYMMETREL is effective in the prophylaxis or treatment
of viral respiratory tract illnesses other than those caused by influenza A virus strains.
Parkinson’s Disease/Syndrome
SYMMETREL is indicated in the treatment of idiopathic Parkinson’s disease (Paralysis Agitans),
postencephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous
system by carbon monoxide intoxication. It is indicated in those elderly patients believed to develop
parkinsonism in association with cerebral arteriosclerosis. In the treatment of Parkinson’s disease,
SYMMETREL is less effective than levodopa, (-)-3-(3,4-dihydroxyphenyl)-L-alanine, and its efficacy
in comparison with the anticholinergic antiparkinson drugs has not yet been established.
Drug-Induced Extrapyramidal Reactions
SYMMETREL is indicated in the treatment of drug-induced extrapyramidal reactions. Although
anticholinergic-type side effects have been noted with SYMMETREL when used in patients with drug-
induced extrapyramidal reactions, there is a lower incidence of these side effects than that observed
with the anticholinergic antiparkinson drugs.
CONTRAINDICATIONS
SYMMETREL is contraindicated in patients with known hypersensitivity to amantadine hydrochloride
or to any of the other ingredients in SYMMETREL.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-023/S-039
NDA 18-101/S-014
Page 7
WARNINGS
Deaths
Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal dose
was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug
overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac
dysfunction includes arrhythmia, tachycardia and hypertension (see OVERDOSAGE).
Suicide Attempts
Suicide attempts, some of which have been fatal, have been reported in patients treated with
SYMMETREL, many of whom received short courses for influenza treatment or prophylaxis. The
incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood.
Suicide attempts and suicidal ideation have been reported in patients with and without prior history of
psychiatric illness. SYMMETREL can exacerbate mental problems in patients with a history of
psychiatric disorders or substance abuse. Patients who attempt suicide may exhibit abnormal mental
states which include disorientation, confusion, depression, personality changes, agitation, aggressive
behavior, hallucinations, paranoia, other psychotic reactions, and somnolence or insomnia. Because of
the possibility of serious adverse effects, caution should be observed when prescribing SYMMETREL
to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the
benefit of treatment.
CNS Effects
Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased
seizure activity.
Patients receiving SYMMETREL who note central nervous system effects or blurring of vision should
be cautioned against driving or working in situations where alertness and adequate motor coordination
are important.
Other
Patients with a history of congestive heart failure or peripheral edema should be followed closely as
there are patients who developed congestive heart failure while receiving SYMMETREL.
Patients with Parkinson’s disease improving on SYMMETREL should resume normal activities
gradually and cautiously, consistent with other medical considerations, such as the presence of
osteoporosis or phlebothrombosis.
Because SYMMETREL has anticholinergic effects and may cause mydriasis, it should not be given to
patients with untreated angle closure glaucoma.
PRECAUTIONS
SYMMETREL should not be discontinued abruptly in patients with Parkinson’s disease since a few
patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this
medication was suddenly stopped. The dose of anticholinergic drugs or of SYMMETREL should be
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-023/S-039
NDA 18-101/S-014
Page 8
reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation
may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety,
depression and slurred speech.
Neuroleptic Malignant Syndrome (NMS)
Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association
with dose reduction or withdrawal of SYMMETREL therapy. Therefore, patients should be observed
carefully when the dosage of SYMMETREL is reduced abruptly or discontinued, especially if the
patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia;
neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental
status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or
hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis,
myoglobinuria, and increased serum myoglobin.
The early diagnosis of this condition is important for the appropriate management of these patients.
Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia,
systemic infection, etc.) is essential. This may be especially complex if the clinical presentation
includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and
symptoms (EPS). Other important considerations in the differential diagnosis include central
anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring,
and 2) treatment of any concomitant serious medical problems for which specific treatments are
available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene are
often used in the treatment of NMS, however, their effectiveness has not been demonstrated in
controlled studies.
Renal disease
Because SYMMETREL is mainly excreted in the urine, it accumulates in the plasma and in the body
when renal function declines. Thus, the dose of SYMMETREL should be reduced in patients with
renal impairment and in individuals who are 65 years of age or older (see DOSAGE AND
ADMINISTRATION; Dosage for Impaired Renal Function).
Liver disease
Care should be exercised when administering SYMMETREL to patients with liver disease. Rare
instances of reversible elevation of liver enzymes have been reported in patients receiving
SYMMETREL, though a specific relationship between the drug and such changes has not been
established.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-023/S-039
NDA 18-101/S-014
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Other
The dose of SYMMETREL may need careful adjustment in patients with congestive heart failure,
peripheral edema, or orthostatic hypotension. Care should be exercised when administering
SYMMETREL to patients with a history of recurrent eczematoid rash, or to patients with psychosis or
severe psychoneurosis not controlled by chemotherapeutic agents.
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as
complications during the course of influenza. SYMMETREL has not been shown to prevent such
complications.
Information for Patients
Patients should be advised of the following information:
Blurry vision and/or impaired mental acuity may occur.
Gradually increase physical activity as the symptoms of Parkinson’s disease improve.
Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness,
confusion, lightheadedness and orthostatic hypotension.
Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs,
notify physician.
Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness
of breath occur.
Do not take more medication than prescribed because of the risk of overdose. If there is no
improvement in a few days, or if medication appears less effective after a few weeks, discuss with a
physician.
Consult physician before discontinuing medication.
Seek medical attention immediately if it is suspected that an overdose of medication has been taken.
Drug Interactions
Careful observation is required when SYMMETREL is administered concurrently with central nervous
system stimulants.
Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of
amantadine.
Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with
Parkinson’s disease, however, it is not known if other phenothiazines produce a similar response.
Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine
concentration in a 61-year-old man receiving SYMMETREL (Amantadine Hydrochloride, USP) 100
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NDA 16-023/S-039
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mg TID for Parkinson’s disease.1 It is not known which of the components of Dyazide contributed to
the observation or if related drugs produce a similar response.
Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of
amantadine by about 30%.
The concurrent use of SYMMETREL with live attenuated influenza vaccine (LAIV) intranasal has not
been evaluated. However, because of the potential for interference between these products, LAIV
should not be administered within 2 weeks before or 48 hours after administration of SYMMETREL,
unless medically indicated. The concern about possible interference arises from the potential for
antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can
be administered at any time relative to use of SYMMETREL.
Carcinogenesis and Mutagenesis
Long-term in vivo animal studies designed to evaluate the carcinogenic potential of SYMMETREL
have not been performed. In several in vitro assays for gene mutation, SYMMETREL did not increase
the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames
Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed
either with or without a liver metabolic activation extract. Further, there was no evidence of
chromosome damage observed in an in vitro test using freshly derived and stimulated human
peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone
marrow micronucleus test (140-550 mg/kg; estimated human equivalent doses of 11.7-45.8 mg/kg
based on body surface area conversion).
Impairment of Fertility
The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under
Good Laboratory Practice (GLP) and according to current recommended methodology. In a three litter,
non-GLP, reproduction study in rats, Symmetrel at a dose of 32 mg/kg/day (equal to the maximum
recommended human dose on a mg/m2 basis) administered to both males and females slightly
impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the
maximum recommended human dose on a mg/m2 basis); intermediate doses were not tested.
Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor
ingested amantadine 2 weeks prior to, and during the IVF cycle.
Pregnancy Category C
The effect of amantadine on embryofetal and peri-postnatal development has not been adequately
tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current
recommended methodology. However, in two non-GLP studies in rats in which females were dosed
from 5 days prior to mating to Day 6 of gestation or on Days 7-14 of gestation, Symmetrel produced
increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended
human dose on a mg/m2 basis). In the non-GLP rat study in which females were dosed on Days 7-14
of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of
50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-023/S-039
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mg/m2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum
recommended human dose on a mg/m2 basis). The safety margins reported may not accurately reflect
the risk considering the questionable quality of the study on which they are based. There are no
adequate and well-controlled studies in pregnant women. Human data regarding teratogenicity after
maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype)
occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7
days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with
pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered
during the first 2 weeks of pregnancy. SYMMETREL should be used during pregnancy only if the
potential benefit justifies the potential risk to the embryo or fetus.
Nursing Mothers
SYMMETREL is excreted in human milk. Use is not recommended in nursing mothers.
Pediatric Use
The safety and efficacy of SYMMETREL in newborn infants and infants below the age of 1 year have
not been established.
Usage in the Elderly
Because SYMMETREL is primarily excreted in the urine, it accumulates in the plasma and in the body
when renal function declines. Thus, the dose of SYMMETREL should be reduced in patients with
renal impairment and in individuals who are 65 years of age or older. The dose of SYMMETREL may
need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension
(see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
The adverse reactions reported most frequently at the recommended dose of SYMMETREL (5-10%)
are: nausea, dizziness (lightheadedness), and insomnia.
Less frequently (1-5%) reported adverse reactions are: depression, anxiety and irritability,
hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral
edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality, agitation, dry
nose, diarrhea and fatigue.
Infrequently (0.1-1%) occurring adverse reactions are: congestive heart failure, psychosis, urinary
retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking abnormality,
amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance, including punctate
subepithelial or other corneal opacity, corneal edema, decreased visual acuity, sensitivity to light, and
optic nerve palsy.
Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia,
neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal
ideation (see WARNINGS).
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NDA 16-023/S-039
NDA 18-101/S-014
Page 12
Other adverse reactions reported during postmarketing experience with SYMMETREL usage include:
Nervous System/Psychiatric
coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction,
manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, and
tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations,
paranoid reaction, stupor, anxiety, depression and slurred speech;
Cardiovascular
cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia;
Respiratory
acute respiratory failure, pulmonary edema, and tachypnea;
Gastrointestinal
dysphagia;
Hematologic
leukocytosis; agranulocytosis
Special Senses
keratitis and mydriasis;
Skin and Appendages
pruritus and diaphoresis;
Miscellaneous
neuroleptic malignant syndrome (see WARNINGS), allergic reactions including anaphylactic
reactions, edema, and fever;
Laboratory Test
elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and
SGPT.
OVERDOSAGE
Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal dose
was 1 gram. Because some patients have attempted suicide by overdosing with amantadine,
prescriptions should be written for the smallest quantity consistent with good patient management.
Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has
resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes
arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including adult
respiratory distress syndrome - ARDS) have been reported; renal dysfunction including increased
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NDA 16-023/S-039
NDA 18-101/S-014
Page 13
BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects
that have been reported include insomnia, anxiety, agitation, aggressive behavior, hypertonia,
hyperkinesia, ataxia, gait abnormality, tremor, confusion, disorientation, depersonalization, fear,
delirium, hallucinations, psychotic reactions, lethargy, somnolence and coma. Seizures may be
exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in
cases where a drug overdose has occurred.
There is no specific antidote for an overdose of SYMMETREL. However, slowly administered
intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg doses
in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported to be
effective in the control of central nervous system toxicity caused by amantadine hydrochloride. For
acute overdosing, general supportive measures should be employed along with immediate gastric
lavage or induction of emesis. Fluids should be forced, and if necessary, given intravenously. The pH
of the urine has been reported to influence the excretion rate of SYMMETREL. Since the excretion
rate of SYMMETREL increases rapidly when the urine is acidic, the administration of urine acidifying
drugs may increase the elimination of the drug from the body. The blood pressure, pulse, respiration
and temperature should be monitored. The patient should be observed for hyperactivity and
convulsions; if required, sedation, and anticonvulsant therapy should be administered. The patient
should be observed for the possible development of arrhythmias and hypotension; if required,
appropriate antiarrhythmic and antihypotensive therapy should be given. Electrocardiographic
monitoring may be required after ingestion, since malignant tachyarrhythmias can appear after
overdose.
Care should be exercised when administering adrenergic agents, such as isoproterenol, to patients with
a SYMMETREL overdose, since the dopaminergic activity of SYMMETREL has been reported to
induce malignant arrhythmias.
The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of recent
voiding, catheterization should be done.
DOSAGE AND ADMINISTRATION
The dose of SYMMETREL (Amantadine Hydrochloride, USP) may need reduction in patients with
congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function (see
Dosage for Impaired Renal Function).
Dosage for Prophylaxis and Treatment of Uncomplicated Influenza A Virus
Illness
Adult
The adult daily dosage of SYMMETREL is 200 mg; two 100 mg tablets (or four teaspoonfuls of
syrup) as a single daily dose. The daily dosage may be split into one tablet of 100 mg (or two
teaspoonfuls of syrup) twice a day. If central nervous system effects develop in once-a-day dosage, a
split dosage schedule may reduce such complaints. In persons 65 years of age or older, the daily
dosage of SYMMETREL is 100 mg.
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NDA 16-023/S-039
NDA 18-101/S-014
Page 14
A 100 mg daily dose has also been shown in experimental challenge studies to be effective as
prophylaxis in healthy adults who are not at high risk for influenza-related complications. However, it
has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily dose for
prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute influenza illness. In
recent clinical trials, the incidence of central nervous system (CNS) side effects associated with the
100 mg daily dose was at or near the level of placebo. The 100 mg dose is recommended for persons
who have demonstrated intolerance to 200 mg of SYMMETREL daily because of CNS or other
toxicities.
Pediatric Patients: 1 yr.-9 yrs. of age
The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day), but
not to exceed 150 mg per day.
9 yrs.-12 yrs. of age
The total daily dose is 200 mg given as one tablet of 100 mg (or two teaspoonfuls of syrup) twice a
day. The 100 mg daily dose has not been studied in this pediatric population. Therefore, there are no
data which demonstrate that this dose is as effective as or is safer than the 200 mg daily dose in this
patient population.
Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or after
contact with individuals with influenza A virus respiratory tract illness.
SYMMETREL should be continued daily for at least 10 days following a known exposure. If
SYMMETREL is used chemoprophylactically in conjunction with inactivated influenza A virus
vaccine until protective antibody responses develop, then it should be administered for 2 to 4 weeks
after the vaccine has been given. When inactivated influenza A virus vaccine is unavailable or
contraindicated, SYMMETREL should be administered for the duration of known influenza A in the
community because of repeated and unknown exposure.
Treatment of influenza A virus illness should be started as soon as possible, preferably within 24 to 48
hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after the
disappearance of signs and symptoms.
Dosage for Parkinsonism
Adult
The usual dose of SYMMETREL is 100 mg twice a day when used alone. SYMMETREL has an onset
of action usually within 48 hours.
The initial dose of SYMMETREL is 100 mg daily for patients with serious associated medical
illnesses or who are receiving high doses of other antiparkinson drugs. After one to several weeks at
100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-023/S-039
NDA 18-101/S-014
Page 15
Occasionally, patients whose responses are not optimal with SYMMETREL at 200 mg daily may
benefit from an increase up to 400 mg daily in divided doses. However, such patients should be
supervised closely by their physicians.
Patients initially deriving benefit from SYMMETREL not uncommonly experience a fall-off of
effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg daily.
Alternatively, temporary discontinuation of SYMMETREL for several weeks, followed by reinitiation
of the drug, may result in regaining benefit in some patients. A decision to use other antiparkinson
drugs may be necessary.
Dosage for Concomitant Therapy
Some patients who do not respond to anticholinergic antiparkinson drugs may respond to
SYMMETREL. When SYMMETREL or anticholinergic antiparkinson drugs are each used with
marginal benefit, concomitant use may produce additional benefit.
When SYMMETREL and levodopa are initiated concurrently, the patient can exhibit rapid therapeutic
benefits. SYMMETREL should be held constant at 100 mg daily or twice daily while the daily dose of
levodopa is gradually increased to optimal benefit.
When SYMMETREL is added to optimal well-tolerated doses of levodopa, additional benefit may
result, including smoothing out the fluctuations in improvement which sometimes occur in patients on
levodopa alone. Patients who require a reduction in their usual dose of levodopa because of
development of side effects may possibly regain lost benefit with the addition of SYMMETREL.
Dosage for Drug-Induced Extrapyramidal Reactions
Adult
The usual dose of SYMMETREL is 100 mg twice a day. Occasionally, patients whose responses are
not optimal with SYMMETREL at 200 mg daily may benefit from an increase up to 300 mg daily in
divided doses.
Dosage for Impaired Renal Function
Depending upon creatinine clearance, the following dosage adjustments are recommended:
CREATININE
CLEARANCE
(mL/min/1.73m2)
SYMMETREL
DOSAGE
30-50
200 mg 1st day and 100 mg
each day thereafter
15-29
200 mg 1st day followed by
100 mg on alternate days
<15
200 mg every 7 days
The recommended dosage for patients on hemodialysis is 200 mg every 7 days.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-023/S-039
NDA 18-101/S-014
Page 16
HOW SUPPLIED
SYMMETREL (Amantadine Hydrochloride, USP) is available in light orange, convex curved,
triangular shaped 100 mg tablets with “SYMMETREL” debossed on one side and plain on the other
side as follows:
Bottles of 100
NDC 63481-108-70
As a clear, colorless syrup [each 5 mL (1 teaspoonful) contains 50 mg amantadine hydrochloride] in:
16 oz. (480 mL) bottles
NDC 63481-205-16
Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room
Temperature].
Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).
REFERENCES
1W.W. Wilson and A.H. Rajput, Amantadine-Dyazide Interaction, Can. Med. Assoc. J. 129:974-975,
1983.
2D.F. Casey, N. Engl. J. Med. 298:516, 1978.
3C.D. Berkowitz, J. Pediatr. 95:144, 1979.
Manufactured for:
Endo Pharmaceuticals Inc.
Chadds Ford, PA 19317
SYMMETREL® is a Registered Trademark of Endo Pharmaceuticals Inc.
Copyright © Endo Pharmaceuticals Inc. 2007
Printed in U.S.A.
2007129/February, 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:44:36.768332
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016023s039,018101s014lbl.pdf', 'application_number': 18101, 'submission_type': 'SUPPL ', 'submission_number': 14}
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NDA 18-086/S-060
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STERILE OPHTHALMIC SOLUTION
TIMOPTIC®
0.25% AND 0.5%
(TIMOLOL MALEATE
OPHTHALMIC SOLUTION)
DESCRIPTION
TIMOPTIC (timolol maleate ophthalmic solution) is a non-selective beta-adrenergic receptor blocking
agent. Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-
propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure
and is provided as the levo-isomer. The optical rotation of timolol maleate is:
25°
[α
]
in 1.0N HCl (C = 5%) = –12.2°
(–11.7° to –12.5°).
405 nm
Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is:
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is
soluble in water, methanol, and alcohol. TIMOPTIC is stable at room temperature.
TIMOPTIC Ophthalmic Solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol
maleate in two dosage strengths: Each mL of TIMOPTIC 0.25% contains 2.5 mg of timolol (3.4 mg of
timolol maleate). The pH of the solution is approximately 7.0, and the osmolarity is 274-328 mOsm.
Each mL of TIMOPTIC 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive
ingredients: monobasic and dibasic sodium phosphate, sodium hydroxide to adjust pH, and water for
injection. Benzalkonium chloride 0.01% is added as preservative.
CLINICAL PHARMACOLOGY
Mechanism of Action
Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not
have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic
(membrane-stabilizing) activity.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with
heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor
blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain
adequate cardiac function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance
from unopposed parasympathetic activity. Such an effect in patients with asthma or other
bronchospastic conditions is potentially dangerous.
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NDA 18-086/S-060
Page 4
TIMOPTIC Ophthalmic Solution, when applied topically on the eye, has the action of reducing
elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma. Elevated
intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The
higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and
optic nerve damage.
The onset of reduction in intraocular pressure following administration of TIMOPTIC can usually be
detected within one-half hour after a single dose. The maximum effect usually occurs in one to two
hours and significant lowering of intraocular pressure can be maintained for periods as long as 24
hours with a single dose. Repeated observations over a period of one year indicate that the intraocular
pressure-lowering effect of TIMOPTIC is well maintained.
The precise mechanism of the ocular hypotensive action of TIMOPTIC is not clearly established at this
time. Tonography and fluorophotometry studies in man suggest that its predominant action may be
related to reduced aqueous formation. However, in some studies a slight increase in outflow facility
was also observed.
Pharmacokinetics
In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was
determined following twice daily administration of TIMOPTIC 0.5%. The mean peak plasma
concentration following morning dosing was 0.46 ng/mL and following afternoon dosing was
0.35 ng/mL.
Clinical Studies
In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or
greater, TIMOPTIC 0.25 percent or 0.5 percent administered twice a day produced a greater reduction
in intraocular pressure than 1, 2, 3, or 4 percent pilocarpine solution administered four times a day or
0.5, 1, or 2 percent epinephrine hydrochloride solution administered twice a day.
In these studies, TIMOPTIC was generally well tolerated and produced fewer and less severe side
effects than either pilocarpine or epinephrine. A slight reduction of resting heart rate in some patients
receiving TIMOPTIC (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.
INDICATIONS AND USAGE
TIMOPTIC Ophthalmic Solution is indicated in the treatment of elevated intraocular pressure in
patients with ocular hypertension or open-angle glaucoma.
CONTRAINDICATIONS
TIMOPTIC is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma;
(3) severe chronic obstructive pulmonary disease (see WARNINGS); (4) sinus bradycardia; (5) second
or third degree atrioventricular block; (6) overt cardiac failure (see WARNINGS); (7) cardiogenic
shock; or (8) hypersensitivity to any component of this product.
WARNINGS
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
The same adverse reactions found with systemic administration of beta-adrenergic blocking
agents may occur with topical administration. For example, severe respiratory reactions and
cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely
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NDA 18-086/S-060
Page 5
death in association with cardiac failure, have been reported following systemic or ophthalmic
administration of timolol maleate (see CONTRAINDICATIONS).
Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished
myocardial contractility, and its inhibition of beta-adrenergic receptor blockade may precipitate more
severe failure.
In Patients Without a History of Cardiac Failure continued depression of the myocardium with beta-
blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or
symptom of cardiac failure, TIMOPTIC should be discontinued.
Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or
moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial
asthma or a history of bronchial asthma, in which TIMOPTIC is contraindicated [see
CONTRAINDICATIONS]) should, in general, not receive beta-blockers, including TIMOPTIC.
Major Surgery
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is
controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-
adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical
procedures. Some patients receiving beta-adrenergic receptor blocking agents have experienced
protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat
has also been reported. For these reasons, in patients undergoing elective surgery, some authorities
recommend gradual withdrawal of beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by
sufficient doses of adrenergic agonists.
Diabetes Mellitus
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous
hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or
oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and
symptoms of acute hypoglycemia.
Thyrotoxicosis
Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of
hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid
abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.
PRECAUTIONS
General
Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these
agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms
suggesting reduced cerebral blood flow develop following initiation of therapy with TIMOPTIC,
alternative therapy should be considered.
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NDA 18-086/S-060
Page 6
There have been reports of bacterial keratitis associated with the use of multiple dose containers of
topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in
most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. (See
PRECAUTIONS, Information for Patients.)
Choroidal detachment after filtration procedures has been reported with the administration of aqueous
suppressant therapy (e.g. timolol).
Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of
treatment is to reopen the angle. This requires constricting the pupil. Timolol maleate has little or no
effect on the pupil. TIMOPTIC should not be used alone in the treatment of angle-closure glaucoma.
Anaphylaxis: While taking beta-blockers, patients with a history of atopy or a history of severe
anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic,
or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of
epinephrine used to treat anaphylactic reactions.
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness
consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).
Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis
or myasthenic symptoms.
Information for Patients
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or
surrounding structures.
Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the
dispensing container contacts the eye or surrounding structures, can become contaminated by
common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of
vision may result from using contaminated solutions. (See PRECAUTIONS, General.)
Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular
condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning
the continued use of the present multidose container.
Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary
disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be
advised not to take this product. (See CONTRAINDICATIONS.)
Patients should be advised that TIMOPTIC contains benzalkonium chloride which may be absorbed by
soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses
may be reinserted 15 minutes following TIMOPTIC administration.
Drug Interactions
Although TIMOPTIC used alone has little or no effect on pupil size, mydriasis resulting from
concomitant therapy with TIMOPTIC and epinephrine has been reported occasionally.
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NDA 18-086/S-060
Page 7
Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally
and TIMOPTIC should be observed for potential additive effects of beta-blockade, both systemic and
on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not
recommended.
Calcium antagonists: Caution should be used in the coadministration of beta-adrenergic blocking
agents, such as TIMOPTIC, and oral or intravenous calcium antagonists because of possible
atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with
impaired cardiac function, coadministration should be avoided.
Catecholamine-depleting drugs: Close observation of the patient is recommended when a beta blocker
is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of
possible additive effects and the production of hypotension and/or marked bradycardia, which may
result in vertigo, syncope, or postural hypotension.
Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with
digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction
time.
Quinidine: Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during
combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of
timolol via the P-450 enzyme, CYP2D6.
Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can
follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound
hypertension with ophthalmic timolol maleate.
Injectable epinephrine: (See PRECAUTIONS, General, Anaphylaxis)
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year study of timolol maleate administered orally to rats, there was a statistically significant
increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day
(approximately 42,000 times the systemic exposure following the maximum recommended human
ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to
approximately 14,000 times the maximum recommended human ophthalmic dose.
In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign
and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female
mice at 500 mg/kg/day, (approximately 71,000 times the systemic exposure following the maximum
recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000,
respectively, times the systemic exposure following the maximum recommended human ophthalmic
dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the
uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again
observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with elevations in serum
prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses
of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been
associated with administration of several other therapeutic agents that elevate serum prolactin, but no
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NDA 18-086/S-060
Page 8
correlation between serum prolactin levels and mammary tumors has been established in humans.
Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol
maleate (the maximum recommended human oral dosage), there were no clinically meaningful
changes in serum prolactin.
Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus
test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation
assay (up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or
10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with
tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with
tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to
control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames
test.
Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at
doses up to 21,000 times the systemic exposure following the maximum recommended human
ophthalmic dose.
Pregnancy:
Teratogenic Effects — Pregnancy Category C. Teratogenicity studies with timolol in mice, rats, and
rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum
recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although
delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal
development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following
the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an
increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of
14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in
this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in pregnant women. TIMOPTIC should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Timolol maleate has been detected in human milk following oral and ophthalmic drug administration.
Because of the potential for serious adverse reactions from TIMOPTIC in nursing infants, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and younger
patients.
ADVERSE REACTIONS
The most frequently reported adverse experiences have been burning and stinging upon instillation
(approximately one in eight patients).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-060
Page 9
The following additional adverse experiences have been reported less frequently with ocular
administration of this or other timolol maleate formulations:
BODY AS A WHOLE
Headache, asthenia/fatigue, and chest pain.
CARDIOVASCULAR
Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident,
cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary
edema, edema, claudication, Raynaud's phenomenon, and cold hands and feet.
DIGESTIVE
Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.
IMMUNOLOGIC
Systemic lupus erythematosus.
NERVOUS SYSTEM/PSYCHIATRIC
Dizziness, increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia,
nightmares, behavioral changes and psychic disturbances including depression, confusion,
hallucinations, anxiety, disorientation, nervousness, and memory loss.
SKIN
Alopecia and psoriasiform rash or exacerbation of psoriasis.
HYPERSENSITIVITY
Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria, and
localized and generalized rash.
RESPIRATORY
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory
failure, dyspnea, nasal congestion, cough and upper respiratory infections.
ENDOCRINE
Masked symptoms of hypoglycemia in diabetic patients (see WARNINGS).
SPECIAL SENSES
Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain,
discharge (e.g., crusting), foreign body sensation, itching and tearing, and dry eyes; ptosis; decreased
corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and
diplopia; pseudopemphigoid; choroidal detachment following filtration surgery (see PRECAUTIONS,
General); and tinnitus.
UROGENITAL
Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-060
Page 10
The following additional adverse effects have been reported in clinical experience with ORAL timolol
maleate or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic
timolol maleate: Allergic: Erythematous rash, fever combined with aching and sore throat,
laryngospasm with respiratory distress; Body as a Whole: Extremity pain, decreased exercise tolerance,
weight loss; Cardiovascular: Worsening of arterial insufficiency, vasodilatation; Digestive:
Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis;
Hematologic: Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulocytosis; Endocrine:
Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating;
Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness, diminished
concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome
characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and
decreased performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital:
Urination difficulties.
OVERDOSAGE
There have been reports of inadvertent overdosage with TIMOPTIC Ophthalmic Solution resulting in
systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness,
headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see also ADVERSE
REACTIONS).
Overdosage has been reported with Tablets BLOCADREN* (timolol maleate tablets). A 30 year old
female ingested 650 mg of BLOCADREN (maximum recommended oral daily dose is 60 mg) and
experienced second and third degree heart block. She recovered without treatment but approximately
two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased
pulse rate, and borderline first degree heart block.
An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that
timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed
that timolol did not dialyze readily.
DOSAGE AND ADMINISTRATION
TIMOPTIC Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual
starting dose is one drop of 0.25 percent TIMOPTIC in the affected eye(s) twice a day. If the clinical
response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected
eye(s) twice a day.
Since in some patients the pressure-lowering response to TIMOPTIC may require a few weeks to
stabilize, evaluation should include a determination of intraocular pressure after approximately 4
weeks of treatment with TIMOPTIC.
If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to
one drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure,
satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure
at different times during the day.
Dosages above one drop of 0.5 percent TIMOPTIC twice a day generally have not been shown to
produce further reduction in intraocular pressure. If the patient's intraocular pressure is still not at a
satisfactory level on this regimen, concomitant therapy with other agent(s) for lowering intraocular
This label may not be the latest approved by FDA.
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NDA 18-086/S-060
Page 11
pressure can be instituted. The concomitant use of two topical beta-adrenergic blocking agents is not
recommended. (See PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)
HOW SUPPLIED
Sterile Ophthalmic Solution TIMOPTIC is a clear, colorless to light yellow solution.
No. 8895 — TIMOPTIC Ophthalmic Solution, 0.25% timolol equivalent, is supplied in an
OCUMETER®* PLUS container, a translucent, natural HDPE plastic ophthalmic dispenser with a
white polystyrene cap with color coded label, and a controlled drop tip as follows:
NDC 0006-8895-35, 5 mL in a 7.5 mL bottle
NDC 0006-8895-36, 10 mL in an 18 mL bottle.
No. 8896 — TIMOPTIC Ophthalmic Solution, 0.5% timolol equivalent, is supplied in an
OCUMETER® PLUS container, a translucent, natural HDPE plastic ophthalmic dispenser with a white
polystyrene cap with color coded label, and a controlled drop tip as follows:
NDC 0006-8896-35, 5 mL in a 7.5 mL bottle
NDC 0006-8896-36, 10 mL in an 18 mL bottle.
Storage
Store at room temperature, 15-30°C (59-86°F). Protect from freezing. Protect from light.
By: Laboratories Merck Sharp & Dohme-Chibret
63963 Clermont-Ferrand Cedex 9, France
Issued September 2002
Printed in USA
170A-04/03 513588Z
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-060
Page 12
STERILE OPHTHALMIC SOLUTION
TIMOPTIC®
0.25% AND 0.5%
(TIMOLOL MALEATE
OPHTHALMIC SOLUTION)
INSTRUCTIONS FOR USE
Please follow these instructions carefully when using TIMOPTIC*. Use TIMOPTIC as prescribed by
your doctor.
1. If you use other topically applied ophthalmic medications, they should be administered at least 10
minutes before or after TIMOPTIC.
2. Wash hands before each use.
3. Before using the medication for the first time, be sure the Safety Strip on the front of the bottle is
unbroken. A gap between the bottle and the cap is normal for an unopened bottle.
4. Tear off the Safety Strip to break the seal.
5. To open the bottle, unscrew the cap by turning as indicated by the arrows.
Opening Arrows 4
Safety Strip4
Gap4
Finger Push Area4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-060
Page 13
6. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid
and your eye.
7. Invert the bottle, and press lightly with the thumb or index finger over the “Finger Push Area” (as
shown) until a single drop is dispensed into the eye as directed by your doctor.
DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.
Ophthalmic medications, if handled improperly, can become contaminated by common bacteria
known to cause eye infections. Serious damage to the eye and subsequent loss of vision may result
from using contaminated ophthalmic medications. If you think your medication may be
contaminated, or if you develop an eye infection, contact your doctor immediately concerning
continued use of this bottle.
8. Repeat steps 6 & 7 with the other eye if instructed to do so by your doctor.
9. Replace the cap by turning until it is firmly touching the bottle. Do not overtighten the cap.
Finger Push Area4
w Finger Push Area
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-060
Page 14
10. The dispenser tip is designed to provide a pre-measured drop; therefore, do NOT enlarge the hole
of the dispenser tip.
11. After you have used all doses, there will be some TIMOPTIC left in the bottle. You should not be
concerned since an extra amount of TIMOPTIC has been added and you will get the full amount of
TIMOPTIC that your doctor prescribed. Do not attempt to remove excess medicine from the bottle.
WARNING: KEEP OUT OF REACH OF CHILDREN.
IF YOU HAVE ANY QUESTIONS ABOUT THE USE OF TIMOPTIC, PLEASE CONSULT YOUR DOCTOR.
*Registered trademark of MERCK & CO., Inc.
MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 2001
Whitehouse Station, NJ 08889, USA
All rights reserved
Issued September 2002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:36.823631
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18086scs060_timoptic_lbl.pdf', 'application_number': 18086, 'submission_type': 'SUPPL ', 'submission_number': 60}
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11,161
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Endo logo (scripted)
ENDO LABORATORIES
SYMMETREL®
(Amantadine Hydrochloride, USP)
Tablets and Syrup
Rx only
DESCRIPTION
SYMMETREL (Amantadine Hydrochloride, USP) is designated generically as amantadine
hydrochloride and chemically as 1-adamantanamine hydrochloride.
• HCl
NH2
Amantadine hydrochloride is a stable white or nearly white crystalline powder, freely soluble in
water and soluble in alcohol and in chloroform.
Amantadine hydrochloride has pharmacological actions as both an anti-Parkinson and an
antiviral drug.
SYMMETREL is available in tablets and syrup.
Each tablet intended for oral administration contains 100 mg amantadine hydrochloride and has
the following inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate,
microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6.
SYMMETREL syrup contains 50 mg of amantadine hydrochloride per 5 mL and has the
following inactive ingredients: artificial raspberry flavor, citric acid, methylparaben,
propylparaben, and sorbitol solution.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Mechanism of Action: Antiviral
The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It
appears to mainly prevent the release of infectious viral nucleic acid into the host cell by
interfering with the function of the transmembrane domain of the viral M2 protein. In certain
cases, amantadine is also known to prevent virus assembly during virus replication. It does not
appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.
Antiviral Activity:
Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e.,
H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A
quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine
and the clinical response to therapy has not been established in man. Sensitivity test results,
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
expressed as the concentration of amantadine required to inhibit by 50% the growth of virus
(ED50) in tissue culture vary greatly (from 0.1 µg/mL to 25.0 µg/mL) depending upon the assay
protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell
type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of
100 µg/mL.
Drug Resistance:
Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from
epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with
reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza
illness. The quantitative relationship between the in vitro sensitivity of influenza A variants to
amantadine and the clinical response to therapy has not been established.
Mechanism of Action: Parkinson’s Disease
The mechanism of action of amantadine in the treatment of Parkinson’s disease and drug-
induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that
SYMMETREL may have direct and indirect effects on dopamine neurons. More recent studies
have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (Ki =
10µM). Although amantadine has not been shown to possess direct anticholinergic activity in
animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary
retention, and constipation.
Pharmacokinetics
SYMMETREL is well absorbed orally. Maximum plasma concentrations are directly related to
dose for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than
proportional increase in maximum plasma concentrations. It is primarily excreted unchanged in
the urine by glomerular filtration and tubular secretion. Eight metabolites of amantadine have
been identified in human urine. One metabolite, an N-acetylated compound, was quantified in
human urine and accounted for 5-15% of the administered dose. Plasma acetylamantadine
accounted for up to 80% of the concurrent amantadine plasma concentration in 5 of 12 healthy
volunteers following the ingestion of a 200 mg dose of amantadine. Acetylamantadine was not
detected in the plasma of the remaining seven volunteers. The contribution of this metabolite to
efficacy or toxicity is not known.
There appears to be a relationship between plasma amantadine concentrations and toxicity. As
concentration increases, toxicity seems to be more prevalent, however, absolute values of
amantadine concentrations associated with adverse effects have not been fully defined.
Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral
administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD
maximum plasma concentration was 0.22 ± 0.03 µg/mL (range: 0.18 to 0.32 µg/mL). The time to
peak concentration was 3.3 ± 1.5 hours (range: 1.5 to 8.0 hours). The apparent oral clearance was
0.28 ± 0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25
hours). Across other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to
31 hours) in 19 healthy volunteers.
After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers,
the mean ± SD maximum plasma concentration Cmax was 0.24 ± 0.04 µg/mL and ranged from
0.18 to 0.28 µg/mL. After 15 days of amantadine 100 mg b.i.d., the Cmax was 0.47 ± 0.11 µg/mL
in four of the five volunteers. The administration of amantadine tablets as a 200 mg single dose
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
to 6 healthy subjects resulted in a Cmax of 0.51 ± 0.14 µg/mL. Across studies, the time to Cmax
(Tmax) averaged about 2 to 4 hours.
Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to
25 mg intravenous doses of amantadine to 15 healthy volunteers.
In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma
clearance was 0.79 ± 0.17 (mean ± SD).
The volume of distribution determined after the intravenous administration of amantadine to 15
healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg
doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal
mucus at mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 µg/g at 1, 4, and
8 hours after dosing, respectively. These concentrations represented 31 ± 33%, 59 ± 61%, and 95
± 86% of the corresponding plasma amantadine concentrations. Amantadine is approximately
67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. Following the
administration of amantadine 100 mg as a single dose, the mean ± SD red blood cell to plasma
ratio ranged from 2.7 ± 0.5 in 6 healthy subjects to 1.4 ± 0.2 in 8 patients with renal
insufficiency.
The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma
concentrations are increased in healthy elderly individuals age 60 and older. After single dose
administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma
clearance of amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life
was 29 ± 7 hours (range 20 to 41 hours). Whether these changes are due to decline in renal
function or other age related factors is not known.
In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for
body mass index, was 1.5 fold higher in males compared to females (p<0.032).
Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly
reduced in adult patients with renal insufficiency. The elimination half-life increases two to three
fold or greater when creatinine clearance is less than 40 mL/min/1.73 m2 and averages eight days
in patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts
by hemodialysis.
The pH of the urine has been reported to influence the excretion rate of SYMMETREL. Since
the excretion rate of SYMMETREL increases rapidly when the urine is acidic, the administration
of urine acidifying drugs may increase the elimination of the drug from the body.
INDICATIONS AND USAGE
SYMMETREL is indicated for the prophylaxis and treatment of signs and symptoms of infection
caused by various strains of influenza A virus. SYMMETREL is also indicated in the treatment
of parkinsonism and drug-induced extrapyramidal reactions.
Influenza A Prophylaxis
SYMMETREL (Amantadine Hydrochloride, USP) is indicated for chemoprophylaxis against
signs and symptoms of influenza A virus infection when early vaccination is not feasible or
when the vaccine is contraindicated or not available. In the prophylaxis of influenza, early
vaccination on an annual basis as recommended by the Centers for Disease Control’s
Immunization Practices Advisory Committee is the method of choice. Because SYMMETREL
does not completely prevent the host immune response to influenza A infection, individuals who
take this drug may still develop immune responses to natural disease or vaccination and may be
3
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For current labeling information, please visit https://www.fda.gov/drugsatfda
protected when later exposed to antigenically related viruses. Following vaccination during an
influenza A outbreak, SYMMETREL prophylaxis should be considered for the 2- to 4-week time
period required to develop an antibody response.
Influenza A Treatment
SYMMETREL is also indicated in the treatment of uncomplicated respiratory tract illness caused
by influenza A virus strains especially when administered early in the course of illness. There are
no well-controlled clinical studies demonstrating that treatment with SYMMETREL will avoid
the development of influenza A virus pneumonitis or other complications in high risk patients.
There is no clinical evidence indicating that SYMMETREL is effective in the prophylaxis or
treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains.
Parkinson’s Disease/Syndrome
SYMMETREL is indicated in the treatment of idiopathic Parkinson’s disease (Paralysis
Agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow
injury to the nervous system by carbon monoxide intoxication. It is indicated in those elderly
patients believed to develop parkinsonism in association with cerebral arteriosclerosis. In the
treatment of Parkinson’s disease, SYMMETREL is less effective than levodopa, (-)-3-(3,4-
dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic
antiparkinson drugs has not yet been established.
Drug-Induced Extrapyramidal Reactions
SYMMETREL is indicated in the treatment of drug-induced extrapyramidal reactions. Although
anticholinergic-type side effects have been noted with SYMMETREL when used in patients with
drug-induced extrapyramidal reactions, there is a lower incidence of these side effects than that
observed with the anticholinergic antiparkinson drugs.
CONTRAINDICATIONS
SYMMETREL is contraindicated in patients with known hypersensitivity to amantadine
hydrochloride or to any of the other ingredients in SYMMETREL.
WARNINGS
Deaths
Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal
dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine.
Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity.
Cardiac dysfunction includes arrhythmia, tachycardia and hypertension (see OVERDOSAGE).
Suicide Attempts
Suicide attempts, some of which have been fatal, have been reported in patients treated with
SYMMETREL, many of whom received short courses for influenza treatment or prophylaxis.
The incidence of suicide attempts is not known and the pathophysiologic mechanism is not
understood. Suicide attempts and suicidal ideation have been reported in patients with and
without prior history of psychiatric illness. SYMMETREL can exacerbate mental problems in
patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide
may exhibit abnormal mental states which include disorientation, confusion, depression,
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic
reactions, and somnolence or insomnia. Because of the possibility of serious adverse effects,
caution should be observed when prescribing SYMMETREL to patients being treated with drugs
having CNS effects, or for whom the potential risks outweigh the benefit of treatment.
CNS Effects
Patients with a history of epilepsy or other “seizures” should be observed closely for possible
increased seizure activity.
Patients receiving SYMMETREL who note central nervous system effects or blurring of vision
should be cautioned against driving or working in situations where alertness and adequate motor
coordination are important.
Other
Patients with a history of congestive heart failure or peripheral edema should be followed closely
as there are patients who developed congestive heart failure while receiving SYMMETREL.
Patients with Parkinson’s disease improving on SYMMETREL should resume normal activities
gradually and cautiously, consistent with other medical considerations, such as the presence of
osteoporosis or phlebothrombosis.
Because SYMMETREL has anticholinergic effects and may cause mydriasis, it should not be
given to patients with untreated angle closure glaucoma.
PRECAUTIONS
SYMMETREL should not be discontinued abruptly in patients with Parkinson’s disease since a
few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration,
when this medication was suddenly stopped. The dose of anticholinergic drugs or of
SYMMETREL should be reduced if atropine-like effects appear when these drugs are used
concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions,
hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.
Neuroleptic Malignant Syndrome (NMS)
Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in
association with dose reduction or withdrawal of SYMMETREL therapy. Therefore, patients
should be observed carefully when the dosage of SYMMETREL is reduced abruptly or
discontinued, especially if the patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia;
neurologic findings including muscle rigidity, involuntary movements, altered consciousness;
mental status changes; other disturbances such as autonomic dysfunction, tachycardia,
tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation,
leukocytosis, myoglobinuria, and increased serum myoglobin.
The early diagnosis of this condition is important for the appropriate management of these
patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g.,
pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical
presentation includes both serious medical illness and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central
nervous system (CNS) pathology.
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The management of NMS should include: 1) intensive symptomatic treatment and medical
monitoring, and 2) treatment of any concomitant serious medical problems for which specific
treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such
as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been
demonstrated in controlled studies.
Renal disease
Because SYMMETREL is mainly excreted in the urine, it accumulates in the plasma and in the
body when renal function declines. Thus, the dose of SYMMETREL should be reduced in
patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE
AND ADMINISTRATION; Dosage for Impaired Renal Function).
Liver disease
Care should be exercised when administering SYMMETREL to patients with liver disease. Rare
instances of reversible elevation of liver enzymes have been reported in patients receiving
SYMMETREL, though a specific relationship between the drug and such changes has not been
established.
Other
The dose of SYMMETREL may need careful adjustment in patients with congestive heart
failure, peripheral edema, or orthostatic hypotension. Care should be exercised when
administering SYMMETREL to patients with a history of recurrent eczematoid rash, or to
patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or
occur as complications during the course of influenza. SYMMETREL has not been shown to
prevent such complications.
Information for Patients
Patients should be advised of the following information:
Blurry vision and/or impaired mental acuity may occur.
Gradually increase physical activity as the symptoms of Parkinson’s disease improve.
Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as
dizziness, confusion, lightheadedness and orthostatic hypotension.
Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness
occurs, notify physician.
Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or
shortness of breath occur.
Do not take more medication than prescribed because of the risk of overdose. If there is no
improvement in a few days, or if medication appears less effective after a few weeks, discuss
with a physician.
Consult physician before discontinuing medication.
Seek medical attention immediately if it is suspected that an overdose of medication has been
taken.
Drug Interactions
Careful observation is required when SYMMETREL is administered concurrently with central
nervous system stimulants.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of
amantadine.
Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with
Parkinson’s disease, however, it is not known if other phenothiazines produce a similar response.
Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma
amantadine concentration in a 61-year-old man receiving SYMMETREL (Amantadine
Hydrochloride, USP) 100 mg TID for Parkinson’s disease.1 It is not known which of the
components of Dyazide contributed to the observation or if related drugs produce a similar
response.
Coadministration of quinine or quinidine with amantadine was shown to reduce the renal
clearance of amantadine by about 30%.
Carcinogenesis and Mutagenesis
Long-term in vivo animal studies designed to evaluate the carcinogenic potential of
SYMMETREL have not been performed. In several in vitro assays for gene mutation,
SYMMETREL did not increase the number of spontaneously observed mutations in four strains
of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary
cells) when incubations were performed either with or without a liver metabolic activation
extract. Further, there was no evidence of chromosome damage observed in an in vitro test using
freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic
activation) or in an in vivo mouse bone marrow micronucleus test (140-550 mg/kg; estimated
human equivalent doses of 11.7-45.8 mg/kg based on body surface area conversion).
Impairment of Fertility
The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted
under Good Laboratory Practice (GLP) and according to current recommended methodology. In
a three litter, non-GLP, reproduction study in rats, Symmetrel at a dose of 32 mg/kg/day (equal
to the maximum recommended human dose on a mg/m2 basis) administered to both males and
females slightly impaired fertility. There were no effects on fertility at a dose level of 10
mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis);
intermediate doses were not tested.
Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor
ingested amantadine 2 weeks prior to, and during the IVF cycle.
Pregnancy Category C
The effect of amantadine on embryofetal and peri-postnatal development has not been
adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and
according to current recommended methodology. However, in two non-GLP studies in rats in
which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7-14 of
gestation, Symmetrel produced increases in embryonic death at an oral dose of 100 mg/kg (or 3
times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in
which females were dosed on Days 7-14 of gestation, there was a marked increase in severe
visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times,
respectively, the maximum recommended human dose on a mg/m2 basis). The no-effect dose for
teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2
basis). The safety margins reported may not accurately reflect the risk considering the
questionable quality of the study on which they are based. There are no adequate and well-
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of
amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an
infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days
during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with
pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d)
administered during the first 2 weeks of pregnancy. SYMMETREL should be used during
pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.
Nursing Mothers
SYMMETREL is excreted in human milk. Use is not recommended in nursing mothers.
Pediatric Use
The safety and efficacy of SYMMETREL in newborn infants and infants below the age of 1 year
have not been established.
Usage in the Elderly
Because SYMMETREL is primarily excreted in the urine, it accumulates in the plasma and in
the body when renal function declines. Thus, the dose of SYMMETREL should be reduced in
patients with renal impairment and in individuals who are 65 years of age or older. The dose of
SYMMETREL may need reduction in patients with congestive heart failure, peripheral edema,
or orthostatic hypotension (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
The adverse reactions reported most frequently at the recommended dose of SYMMETREL (5-
10%) are: nausea, dizziness (lightheadedness), and insomnia.
Less frequently (1-5%) reported adverse reactions are: depression, anxiety and irritability,
hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral
edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality,
agitation, dry nose, diarrhea and fatigue.
Infrequently (0.1-1%) occurring adverse reactions are: congestive heart failure, psychosis,
urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking
abnormality, amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance,
including punctate subepithelial or other corneal opacity, corneal edema, decreased visual acuity,
sensitivity to light, and optic nerve palsy.
Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia,
neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal
ideation (see WARNINGS).
Other adverse reactions reported during postmarketing experience with SYMMETREL usage
include:
Nervous System/Psychiatric
coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid
reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG
changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions,
hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech;
8
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Cardiovascular
cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia;
Respiratory
acute respiratory failure, pulmonary edema, and tachypnea;
Gastrointestinal
dysphagia;
Hematologic
leukocytosis;
Special Senses
keratitis and mydriasis;
Skin and Appendages
pruritus and diaphoresis;
Miscellaneous
neuroleptic malignant syndrome (see WARNINGS), allergic reactions including anaphylactic
reactions, edema, and fever;
Laboratory Test
elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and
SGPT.
OVERDOSAGE
Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal
dose was 1 gram. Because some patients have attempted suicide by overdosing with amantadine,
prescriptions should be written for the smallest quantity consistent with good patient
management.
Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose
has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction
includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress
(including adult respiratory distress syndrome - ARDS) have been reported; renal dysfunction
including increased BUN, decreased creatinine clearance and renal insufficiency can occur.
Central nervous system effects that have been reported include insomnia, anxiety, agitation,
aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion,
disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy,
somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure
disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.
There is no specific antidote for an overdose of SYMMETREL. However, slowly administered
intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg
doses in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported
to be effective in the control of central nervous system toxicity caused by amantadine
hydrochloride. For acute overdosing, general supportive measures should be employed along
with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary,
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
given intravenously. The pH of the urine has been reported to influence the excretion rate of
SYMMETREL. Since the excretion rate of SYMMETREL increases rapidly when the urine is
acidic, the administration of urine acidifying drugs may increase the elimination of the drug from
the body. The blood pressure, pulse, respiration and temperature should be monitored. The
patient should be observed for hyperactivity and convulsions; if required, sedation, and
anticonvulsant therapy should be administered. The patient should be observed for the possible
development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and
antihypotensive therapy should be given. Electrocardiographic monitoring may be required after
ingestion, since malignant tachyarrhythmias can appear after overdose.
Care should be exercised when administering adrenergic agents, such as isoproterenol, to
patients with a SYMMETREL overdose, since the dopaminergic activity of SYMMETREL has
been reported to induce malignant arrhythmias.
The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of
recent voiding, catheterization should be done.
DOSAGE AND ADMINISTRATION
The dose of SYMMETREL (Amantadine Hydrochloride, USP) may need reduction in patients
with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal
function (see Dosage for Impaired Renal Function).
Dosage for Prophylaxis and Treatment of Uncomplicated Influenza A Virus Illness
Adult
The adult daily dosage of SYMMETREL is 200 mg; two 100 mg tablets (or four teaspoonfuls of
syrup) as a single daily dose. The daily dosage may be split into one tablet of 100 mg (or two
teaspoonfuls of syrup) twice a day. If central nervous system effects develop in once-a-day
dosage, a split dosage schedule may reduce such complaints. In persons 65 years of age or older,
the daily dosage of SYMMETREL is 100 mg.
A 100 mg daily dose has also been shown in experimental challenge studies to be effective as
prophylaxis in healthy adults who are not at high risk for influenza-related complications.
However, it has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily
dose for prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute
influenza illness. In recent clinical trials, the incidence of central nervous system (CNS) side
effects associated with the 100 mg daily dose was at or near the level of placebo. The 100 mg
dose is recommended for persons who have demonstrated intolerance to 200 mg of
SYMMETREL daily because of CNS or other toxicities.
Pediatric Patients: 1 yr.-9 yrs. of age
The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day),
but not to exceed 150 mg per day.
9 yrs.-12 yrs. of age
The total daily dose is 200 mg given as one tablet of 100 mg (or two teaspoonfuls of syrup) twice
a day. The 100 mg daily dose has not been studied in this pediatric population. Therefore, there
are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily
dose in this patient population.
Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or
after contact with individuals with influenza A virus respiratory tract illness.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SYMMETREL should be continued daily for at least 10 days following a known exposure. If
SYMMETREL is used chemoprophylactically in conjunction with inactivated influenza A virus
vaccine until protective antibody responses develop, then it should be administered for 2 to 4
weeks after the vaccine has been given. When inactivated influenza A virus vaccine is
unavailable or contraindicated, SYMMETREL should be administered for the duration of known
influenza A in the community because of repeated and unknown exposure.
Treatment of influenza A virus illness should be started as soon as possible, preferably within 24
to 48 hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after
the disappearance of signs and symptoms.
Dosage for Parkinsonism
Adult
The usual dose of SYMMETREL is 100 mg twice a day when used alone. SYMMETREL has an
onset of action usually within 48 hours.
The initial dose of SYMMETREL is 100 mg daily for patients with serious associated medical
illnesses or who are receiving high doses of other antiparkinson drugs. After one to several
weeks at 100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary.
Occasionally, patients whose responses are not optimal with SYMMETREL at 200 mg daily may
benefit from an increase up to 400 mg daily in divided doses. However, such patients should be
supervised closely by their physicians.
Patients initially deriving benefit from SYMMETREL not uncommonly experience a fall-off of
effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg
daily. Alternatively, temporary discontinuation of SYMMETREL for several weeks, followed by
reinitiation of the drug, may result in regaining benefit in some patients. A decision to use other
antiparkinson drugs may be necessary.
Dosage for Concomitant Therapy
Some patients who do not respond to anticholinergic antiparkinson drugs may respond to
SYMMETREL. When SYMMETREL or anticholinergic antiparkinson drugs are each used with
marginal benefit, concomitant use may produce additional benefit.
When SYMMETREL and levodopa are initiated concurrently, the patient can exhibit rapid
therapeutic benefits. SYMMETREL should be held constant at 100 mg daily or twice daily while
the daily dose of levodopa is gradually increased to optimal benefit.
When SYMMETREL is added to optimal well-tolerated doses of levodopa, additional benefit
may result, including smoothing out the fluctuations in improvement which sometimes occur in
patients on levodopa alone. Patients who require a reduction in their usual dose of levodopa
because of development of side effects may possibly regain lost benefit with the addition of
SYMMETREL.
Dosage for Drug-Induced Extrapyramidal Reactions
Adult
The usual dose of SYMMETREL is 100 mg twice a day. Occasionally, patients whose responses
are not optimal with SYMMETREL at 200 mg daily may benefit from an increase up to 300 mg
daily in divided doses.
Dosage for Impaired Renal Function
Depending upon creatinine clearance, the following dosage adjustments are recommended:
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
CREATININE CLEARANCE
SYMMETREL DOSAGE
(mL/min/1.73m2)
30-50
200 mg 1st day and 100 mg
each day thereafter
15-29
200 mg 1st day followed by
100 mg on alternate days
<15
200 mg every 7 days
The recommended dosage for patients on hemodialysis is 200 mg every 7 days.
HOW SUPPLIED
SYMMETREL (Amantadine Hydrochloride, USP) is available in light orange, convex curved,
triangular shaped 100 mg tablets with “SYMMETREL” debossed on one side and plain on the
other side as follows:
Bottles of 100
NDC 63481-108-70
As a clear, colorless syrup [each 5 mL (1 teaspoonful) contains 50 mg amantadine
hydrochloride] in:
16 oz. (480 mL) bottles
NDC 63481-205-16
Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room
Temperature].
Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).
REFERENCES
1W.W. Wilson and A.H. Rajput, Amantadine-Dyazide Interaction, Can. Med. Assoc. J. 129:974-
975, 1983.
2D.F. Casey, N. Engl. J. Med. 298:516, 1978.
3C.D. Berkowitz, J. Pediatr. 95:144, 1979.
Manufactured for:
Manufactured by:
Endo Pharmaceuticals Inc. (Endo scripted logo)
Bristol-Myers Squibb
Chadds Ford, PA 19317
Princeton, NJ 08543 USA
SYMMETREL® is a Registered Trademark of Endo Pharmaceuticals Inc.
Copyright © Endo Pharmaceuticals Inc. 2002
Printed in U.S.A.
6475-04/July, 2002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:44:36.882917
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/018101s009lbl.pdf', 'application_number': 18101, 'submission_type': 'SUPPL ', 'submission_number': 9}
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NDA 18-086/S-072
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STERILE OPHTHALMIC SOLUTION
TIMOPTIC®
0.25% AND 0.5%
(TIMOLOL MALEATE
OPHTHALMIC SOLUTION)
DESCRIPTION
TIMOPTIC* (timolol maleate ophthalmic solution) is a non-selective beta-adrenergic receptor blocking agent.
Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1)
(salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-
isomer. The optical rotation of timolol maleate is:
25°
[α]
in 1.0N HCl (C = 5%) = –12.2° (–11.7° to –12.5°).
405 nm
Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is:
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble
in water, methanol, and alcohol. TIMOPTIC is stable at room temperature.
TIMOPTIC Ophthalmic Solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol
maleate in two dosage strengths: Each mL of TIMOPTIC 0.25% contains 2.5 mg of timolol (3.4 mg of timolol
maleate). The pH of the solution is approximately 7.0, and the osmolarity is 274-328 mOsm. Each mL of
TIMOPTIC 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: monobasic and
dibasic sodium phosphate, sodium hydroxide to adjust pH, and water for injection. Benzalkonium chloride 0.01%
is added as preservative.
CLINICAL PHARMACOLOGY
Mechanism of Action
Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have
significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing)
activity.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart
disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor blockade may
inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac
function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from
unopposed parasympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions
is potentially dangerous.
TIMOPTIC Ophthalmic Solution, when applied topically on the eye, has the action of reducing elevated as
well as normal intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is
a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular
pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.
The onset of reduction in intraocular pressure following administration of TIMOPTIC can usually be detected
within one-half hour after a single dose. The maximum effect usually occurs in one to two hours and significant
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1985, 1995 MERCK & CO., Inc.
All rights reserved
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-070
NDA 18-086/S-072
Page 4
lowering of intraocular pressure can be maintained for periods as long as 24 hours with a single dose. Repeated
observations over a period of one year indicate that the intraocular pressure-lowering effect of TIMOPTIC is well
maintained.
The precise mechanism of the ocular hypotensive action of TIMOPTIC is not clearly established at this time.
Tonography and fluorophotometry studies in man suggest that its predominant action may be related to reduced
aqueous formation. However, in some studies a slight increase in outflow facility was also observed.
Pharmacokinetics
In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined
following twice daily administration of TIMOPTIC 0.5%. The mean peak plasma concentration following morning
dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL.
Clinical Studies
In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater,
TIMOPTIC 0.25 percent or 0.5 percent administered twice a day produced a greater reduction in intraocular
pressure than 1, 2, 3, or 4 percent pilocarpine solution administered four times a day or 0.5, 1, or 2 percent
epinephrine hydrochloride solution administered twice a day.
In these studies, TIMOPTIC was generally well tolerated and produced fewer and less severe side effects
than either pilocarpine or epinephrine. A slight reduction of resting heart rate in some patients receiving
TIMOPTIC (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.
INDICATIONS AND USAGE
TIMOPTIC Ophthalmic Solution is indicated in the treatment of elevated intraocular pressure in patients with
ocular hypertension or open-angle glaucoma.
CONTRAINDICATIONS
TIMOPTIC is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma;
(3) severe chronic obstructive pulmonary disease (see WARNINGS); (4) sinus bradycardia; (5) second or third
degree atrioventricular block; (6) overt cardiac failure (see WARNINGS); (7) cardiogenic shock; or
(8) hypersensitivity to any component of this product.
WARNINGS
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
The same adverse reactions found with systemic administration of beta-adrenergic blocking agents
may occur with topical administration. For example, severe respiratory reactions and cardiac reactions,
including death due to bronchospasm in patients with asthma, and rarely death in association with
cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate
(see CONTRAINDICATIONS).
Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished
myocardial contractility, and its inhibition of beta-adrenergic receptor blockade may precipitate more severe
failure.
In Patients Without a History of Cardiac Failure continued depression of the myocardium with beta-blocking
agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac
failure, TIMOPTIC should be discontinued.
Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or
moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma
or a history of bronchial asthma, in which TIMOPTIC is contraindicated [see CONTRAINDICATIONS]) should, in
general, not receive beta-blockers, including TIMOPTIC.
Major Surgery
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is
controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-
adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures.
Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted severe
hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For
these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of
beta-adrenergic receptor blocking agents.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-070
NDA 18-086/S-072
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If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient
doses of adrenergic agonists.
Diabetes Mellitus
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous
hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral
hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute
hypoglycemia.
Thyrotoxicosis
Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.
Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-
adrenergic blocking agents that might precipitate a thyroid storm.
PRECAUTIONS
General
Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents
should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting
reduced cerebral blood flow develop following initiation of therapy with TIMOPTIC, alternative therapy should be
considered.
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical
ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases,
had a concurrent corneal disease or a disruption of the ocular epithelial surface. (See PRECAUTIONS,
Information for Patients.)
Choroidal detachment after filtration procedures has been reported with the administration of aqueous
suppressant therapy (e.g. timolol).
Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment is to
reopen the angle. This requires constricting the pupil. Timolol maleate has little or no effect on the pupil.
TIMOPTIC should not be used alone in the treatment of angle-closure glaucoma.
Anaphylaxis: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic
reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic
challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to
treat anaphylactic reactions.
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent
with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported
rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.
Information for Patients
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or
surrounding structures.
Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing
container contacts the eye or surrounding structures, can become contaminated by common bacteria known to
cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using
contaminated solutions. (See PRECAUTIONS, General.)
Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular condition
(e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use
of the present multidose container.
Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease,
sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take
this product. (See CONTRAINDICATIONS.)
Patients should be advised that TIMOPTIC contains benzalkonium chloride which may be absorbed by soft
contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be
reinserted 15 minutes following TIMOPTIC administration.
Drug Interactions
Although TIMOPTIC used alone has little or no effect on pupil size, mydriasis resulting from concomitant
therapy with TIMOPTIC and epinephrine has been reported occasionally.
Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and
TIMOPTIC should be observed for potential additive effects of beta-blockade, both systemic and on intraocular
pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-070
NDA 18-086/S-072
Page 6
Calcium antagonists: Caution should be used in the coadministration of beta-adrenergic blocking agents,
such as TIMOPTIC, and oral or intravenous calcium antagonists because of possible atrioventricular conduction
disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function,
coadministration should be avoided.
Catecholamine-depleting drugs: Close observation of the patient is recommended when a beta blocker is
administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible
additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo,
syncope, or postural hypotension.
Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with digitalis and
calcium antagonists may have additive effects in prolonging atrioventricular conduction time.
CYP2D6 inhibitors: Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been
reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and timolol.
Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow
the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with
ophthalmic timolol maleate.
Injectable epinephrine: (See PRECAUTIONS, General, Anaphylaxis)
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase
in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately
42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar
differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the
maximum recommended human ophthalmic dose.
In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and
malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at
500 mg/kg/day, (approximately 71,000 times the systemic exposure following the maximum recommended
human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the
systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in
female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically
significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin
which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or
50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with
administration of several other therapeutic agents that elevate serum prolactin, but no correlation between
serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human
female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended
human oral dosage), there were no clinically meaningful changes in serum prolactin.
Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and
cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to
100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were
associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven
replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent
dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2
is usually considered the criterion for a positive Ames test.
Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses
up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.
Pregnancy:
Teratogenic Effects — Pregnancy Category C. Teratogenicity studies with timolol in mice, rats, and rabbits at
oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended
human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification
was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses
of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human
ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased
fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the
maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in pregnant women. TIMOPTIC should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-070
NDA 18-086/S-072
Page 7
Nursing Mothers
Timolol maleate has been detected in human milk following oral and ophthalmic drug administration.
Because of the potential for serious adverse reactions from TIMOPTIC in nursing infants, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug
to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
ADVERSE REACTIONS
The most frequently reported adverse experiences have been burning and stinging upon instillation
(approximately one in eight patients).
The following additional adverse experiences have been reported less frequently with ocular administration
of this or other timolol maleate formulations:
BODY AS A WHOLE
Headache, asthenia/fatigue, and chest pain.
CARDIOVASCULAR
Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident,
cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema,
edema, claudication, Raynaud's phenomenon, and cold hands and feet.
DIGESTIVE
Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.
IMMUNOLOGIC
Systemic lupus erythematosus.
NERVOUS SYSTEM/PSYCHIATRIC
Dizziness, increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia,
nightmares, behavioral changes and psychic disturbances including depression, confusion, hallucinations,
anxiety, disorientation, nervousness, and memory loss.
SKIN
Alopecia and psoriasiform rash or exacerbation of psoriasis.
HYPERSENSITIVITY
Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria, and
localized and generalized rash.
RESPIRATORY
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure,
dyspnea, nasal congestion, cough and upper respiratory infections.
ENDOCRINE
Masked symptoms of hypoglycemia in diabetic patients (see WARNINGS).
SPECIAL SENSES
Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain, discharge
(e.g., crusting), foreign body sensation, itching and tearing, and dry eyes; ptosis; decreased corneal sensitivity;
cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid;
choroidal detachment following filtration surgery (see PRECAUTIONS, General); and tinnitus.
UROGENITAL
Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.
The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate
or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic timolol maleate:
Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory
distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular:
Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting,
mesenteric arterial thrombosis, ischemic colitis; Hematologic: Nonthrombocytopenic purpura; thrombocytopenic
purpura, agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased
pigmentation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness,
diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome
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characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased
performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties.
OVERDOSAGE
There have been reports of inadvertent overdosage with TIMOPTIC Ophthalmic Solution resulting in
systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness,
headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see also ADVERSE
REACTIONS).
Overdosage has been reported with Tablets BLOCADREN* (timolol maleate tablets). A 30-year-old female
ingested 650 mg of BLOCADREN (maximum recommended oral daily dose is 60 mg) and experienced second
and third degree heart block. She recovered without treatment but approximately two months later developed
irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree
heart block.
An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that timolol
was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not
dialyze readily.
DOSAGE AND ADMINISTRATION
TIMOPTIC Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual starting
dose is one drop of 0.25 percent TIMOPTIC in the affected eye(s) twice a day. If the clinical response is not
adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) twice a day.
Since in some patients the pressure-lowering response to TIMOPTIC may require a few weeks to stabilize,
evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with
TIMOPTIC.
If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to one
drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure, satisfactory
response to the once-a-day dose is best determined by measuring the intraocular pressure at different times
during the day.
Dosages above one drop of 0.5 percent TIMOPTIC twice a day generally have not been shown to produce
further reduction in intraocular pressure. If the patient's intraocular pressure is still not at a satisfactory level on
this regimen, concomitant therapy with other agent(s) for lowering intraocular pressure can be instituted. The
concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See PRECAUTIONS,
Drug Interactions, Beta-adrenergic blocking agents.)
HOW SUPPLIED
Sterile Ophthalmic Solution TIMOPTIC is a clear, colorless to light yellow solution.
No. 8895 — TIMOPTIC Ophthalmic Solution, 0.25% timolol equivalent, is supplied in an OCUMETER®*
PLUS container, a white, translucent, HDPE plastic ophthalmic dispenser with a controlled drop tip and a white
polystyrene cap with yellow label as follows:
NDC 0006-8895-35, 5 mL in a 7.5 mL capacity bottle
No. 8896 — TIMOPTIC Ophthalmic Solution, 0.5% timolol equivalent, is supplied in an OCUMETER® PLUS
container, a white translucent, HDPE plastic ophthalmic dispenser with a controlled drop tip and a white
polystyrene cap with yellow label as follows:
NDC 0006-8896-35, 5 mL in a 7.5 mL capacity bottle
NDC 0006-8896-36, 10 mL in an 18 mL capacity bottle.
Storage
Store at room temperature, 15-30°C (59-86°F). Protect from freezing. Protect from light.
*Registered trademark of MERCK & CO., Inc.
By: Laboratories Merck Sharp & Dohme-Chibret
63963 Clermont-Ferrand Cedex 9, France
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-070
NDA 18-086/S-072
Page 9
Issued September 2005
324A-07/05 514041Z
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
STERILE OPHTHALMIC SOLUTION
TIMOPTIC®
0.25% AND 0.5%
(TIMOLOL MALEATE
OPHTHALMIC SOLUTION)
9391006
INSTRUCTIONS FOR USE
Please follow these instructions carefully when using TIMOPTIC*. Use TIMOPTIC as prescribed by your doctor.
1. If you use other topically applied ophthalmic medications, they should be administered at least 10 minutes
before or after TIMOPTIC.
2. Wash hands before each use.
3. Before using the medication for the first time, be sure the Safety Strip on the front of the bottle is unbroken.
A gap between the bottle and the cap is normal for an unopened bottle.
4. Tear off the Safety Strip to break the seal.
5. To open the bottle, unscrew the cap by turning as indicated by the arrows on the top of the cap. Do not pull
the cap directly up and away from the bottle. Pulling the cap directly up will prevent your dispenser from
operating properly.
Opening Arrows 4
Safety Strip4
Gap4
Finger Push Area4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-070
NDA 18-086/S-072
Page 10
6. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and your
eye.
7. Invert the bottle, and press lightly with the thumb or index finger over the “Finger Push Area” (as shown)
until a single drop is dispensed into the eye as directed by your doctor.
DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.
OPHTHALMIC MEDICATIONS, IF HANDLED IMPROPERLY, CAN BECOME CONTAMINATED BY
COMMON BACTERIA KNOWN TO CAUSE EYE INFECTIONS. SERIOUS DAMAGE TO THE EYE AND
SUBSEQUENT LOSS OF VISION MAY RESULT FROM USING CONTAMINATED OPHTHALMIC
MEDICATIONS. IF YOU THINK YOUR MEDICATION MAY BE CONTAMINATED, OR IF YOU DEVELOP
AN EYE INFECTION, CONTACT YOUR DOCTOR IMMEDIATELY CONCERNING CONTINUED USE OF
THIS BOTTLE.
8. If drop dispensing is difficult after opening for the first time, replace the cap on the bottle and tighten (DO
NOT OVERTIGHTEN) and then remove by turning the cap in the opposite direction as indicated by the
arrows on the top of the cap.
9. Repeat steps 6 & 7 with the other eye if instructed to do so by your doctor.
Finger Push Area4
w Finger Push Area
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NDA 18-086/S-070
NDA 18-086/S-072
Page 11
10. Replace the cap by turning until it is firmly touching the bottle. The arrow on the left side of the cap must be
aligned with the arrow on the left side of the bottle label for proper closure. Do not overtighten or you may
damage the bottle and cap.
11. The dispenser tip is designed to provide a single drop; therefore, do NOT enlarge the hole of the dispenser
tip.
12. After you have used all doses, there will be some TIMOPTIC left in the bottle. You should not be concerned
since an extra amount of TIMOPTIC has been added and you will get the full amount of TIMOPTIC that your
doctor prescribed. Do not attempt to remove excess medicine from the bottle.
WARNING: KEEP OUT OF REACH OF CHILDREN.
IF YOU HAVE ANY QUESTIONS ABOUT THE USE OF TIMOPTIC, PLEASE CONSULT YOUR DOCTOR.
*Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 2001 MERCK & CO., Inc.
All rights reserved
Issued September 2005
By: Laboratories Merck Sharp & Dohme-Chibret
63963 Clermont-Ferrand Cedex 9, France
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-070
NDA 18-086/S-072
Page 12
Cap Label for 0.25%
Container Label for 0.25%, 5 mL size
Cap Label for 0.50%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-086/S-070
NDA 18-086/S-072
Page 13
Container Label for 0.50%, 5 mL size
Container Label for 0.50%, 10 mL size
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018086s070s072lbl.pdf', 'application_number': 18086, 'submission_type': 'SUPPL ', 'submission_number': 70}
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SYMMETREL®
(Amantadine Hydrochloride, USP)
Tablets and Syrup
Rx only
DESCRIPTION
SYMMETREL (Amantadine Hydrochloride, USP) is designated generically as amantadine
hydrochloride and chemically as 1-adamantanamine hydrochloride.
• HCl
Chemical Structure
Amantadine hydrochloride is a stable white or nearly white crystalline powder, freely soluble in
water and soluble in alcohol and in chloroform.
Amantadine hydrochloride has pharmacological actions as both an anti-Parkinson and an
antiviral drug.
SYMMETREL is available in tablets and syrup.
Each tablet intended for oral administration contains 100 mg amantadine hydrochloride and has
the following inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate,
microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6.
SYMMETREL syrup contains 50 mg of amantadine hydrochloride per 5 mL and has the
following inactive ingredients: artificial raspberry flavor, citric acid, methylparaben,
propylparaben, and sorbitol solution.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Mechanism of Action: Antiviral
The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It
appears to mainly prevent the release of infectious viral nucleic acid into the host cell by
interfering with the function of the transmembrane domain of the viral M2 protein. In certain
cases, amantadine is also known to prevent virus assembly during virus replication. It does not
appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.
1
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Antiviral Activity
Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e.,
H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A
quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine
and the clinical response to therapy has not been established in man. Sensitivity test results,
expressed as the concentration of amantadine required to inhibit by 50% the growth of virus
(ED50) in tissue culture vary greatly (from 0.1 µg/mL to 25.0 µg/mL) depending upon the assay
protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell
type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of
100 µg/mL.
Drug Resistance
Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from
epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with
reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza
illness. The quantitative relationship between the in vitro sensitivity of influenza A variants to
amantadine and the clinical response to therapy has not been established.
Mechanism of Action: Parkinson’s Disease
The mechanism of action of amantadine in the treatment of Parkinson’s disease and drug-
induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that
SYMMETREL may have direct and indirect effects on dopamine neurons. More recent studies
have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (Ki =
10μM). Although amantadine has not been shown to possess direct anticholinergic activity in
animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary
retention, and constipation.
Pharmacokinetics
SYMMETREL is well absorbed orally. Maximum plasma concentrations are directly related to
dose for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than
proportional increase in maximum plasma concentrations. It is primarily excreted unchanged in
the urine by glomerular filtration and tubular secretion. Eight metabolites of amantadine have
been identified in human urine. One metabolite, an N-acetylated compound, was quantified in
human urine and accounted for 5-15% of the administered dose. Plasma acetylamantadine
accounted for up to 80% of the concurrent amantadine plasma concentration in 5 of 12 healthy
volunteers following the ingestion of a 200 mg dose of amantadine. Acetylamantadine was not
detected in the plasma of the remaining seven volunteers. The contribution of this metabolite to
efficacy or toxicity is not known.
There appears to be a relationship between plasma amantadine concentrations and toxicity. As
concentration increases, toxicity seems to be more prevalent, however, absolute values of
amantadine concentrations associated with adverse effects have not been fully defined.
Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral
administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean ± SD
2
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maximum plasma concentration was 0.22 ± 0.03 µg/mL (range: 0.18 to 0.32 µg/mL). The time to
peak concentration was 3.3 ± 1.5 hours (range: 1.5 to 8.0 hours). The apparent oral clearance was
0.28 ± 0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17 ± 4 hours (range: 10 to 25
hours). Across other studies, amantadine plasma half-life has averaged 16 ± 6 hours (range: 9 to
31 hours) in 19 healthy volunteers.
After oral administration of a single dose of 100 mg amantadine syrup to five healthy volunteers,
the mean ± SD maximum plasma concentration Cmax was 0.24 ± 0.04 µg/mL and ranged from
0.18 to 0.28 µg/mL. After 15 days of amantadine 100 mg b.i.d., the Cmax was 0.47 ± 0.11 µg/mL
in four of the five volunteers. The administration of amantadine tablets as a 200 mg single dose
to 6 healthy subjects resulted in a Cmax of 0.51 ± 0.14 µg/mL. Across studies, the time to Cmax
(Tmax) averaged about 2 to 4 hours.
Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to
25 mg intravenous doses of amantadine to 15 healthy volunteers.
In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma
clearance was 0.79 ± 0.17 (mean ± SD).
The volume of distribution determined after the intravenous administration of amantadine to 15
healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg
doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal
mucus at mean ± SD concentrations of 0.15 ± 0.16, 0.28 ± 0.26, and 0.39 ± 0.34 µg/g at 1, 4, and
8 hours after dosing, respectively. These concentrations represented 31 ± 33%, 59 ± 61%, and 95
± 86% of the corresponding plasma amantadine concentrations. Amantadine is approximately
67% bound to plasma proteins over a concentration range of 0.1 to 2.0 µg/mL. Following the
administration of amantadine 100 mg as a single dose, the mean ± SD red blood cell to plasma
ratio ranged from 2.7 ± 0.5 in 6 healthy subjects to 1.4 ± 0.2 in 8 patients with renal
insufficiency.
The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma
concentrations are increased in healthy elderly individuals age 60 and older. After single dose
administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma
clearance of amantadine was 0.10 ± 0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life
was 29 ± 7 hours (range 20 to 41 hours). Whether these changes are due to decline in renal
function or other age related factors is not known.
In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for
body mass index, was 1.5 fold higher in males compared to females (p<0.032).
Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly
reduced in adult patients with renal insufficiency. The elimination half-life increases two to three
fold or greater when creatinine clearance is less than 40 mL/min/1.73 m2 and averages eight days
in patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts
by hemodialysis.
3
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The pH of the urine has been reported to influence the excretion rate of SYMMETREL. Since
the excretion rate of SYMMETREL increases rapidly when the urine is acidic, the administration
of urine acidifying drugs may increase the elimination of the drug from the body.
INDICATIONS AND USAGE
SYMMETREL is indicated for the prophylaxis and treatment of signs and symptoms of infection
caused by various strains of influenza A virus. SYMMETREL is also indicated in the treatment
of parkinsonism and drug-induced extrapyramidal reactions.
Influenza A Prophylaxis
SYMMETREL is indicated for chemoprophylaxis against signs and symptoms of influenza A
virus infection. Because SYMMETREL does not completely prevent the host immune response
to influenza A infection, individuals who take this drug may still develop immune responses to
natural disease or vaccination and may be protected when later exposed to antigenically related
viruses. Following vaccination during an influenza A outbreak, SYMMETREL prophylaxis
should be considered for the 2- to 4-week time period required to develop an antibody response.
Influenza A Treatment
SYMMETREL is also indicated in the treatment of uncomplicated respiratory tract illness caused
by influenza A virus strains especially when administered early in the course of illness. There are
no well-controlled clinical studies demonstrating that treatment with SYMMETREL will avoid
the development of influenza A virus pneumonitis or other complications in high risk patients.
There is no clinical evidence indicating that SYMMETREL is effective in the prophylaxis or
treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains.
The following points should be considered before initiating treatment or prophylaxis with
SYMMETREL:
• SYMMETREL is not a substitute for early vaccination on an annual basis as
recommended by the Centers for Disease Control and Prevention Advisory Committee on
Immunization Practices.
• Influenza viruses change over time. Emergence of resistance mutations could decrease
drug effectiveness. Other factors (for example, changes in viral virulence) might also
diminish clinical benefit of antiviral drugs. Prescribers should consider available
information on influenza drug susceptibility patterns and treatment effects when deciding
whether to use SYMMETREL.
Parkinson’s Disease/Syndrome
SYMMETREL is indicated in the treatment of idiopathic Parkinson’s disease (Paralysis
Agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow
injury to the nervous system by carbon monoxide intoxication. It is indicated in those elderly
patients believed to develop parkinsonism in association with cerebral arteriosclerosis. In the
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
treatment of Parkinson’s disease, SYMMETREL is less effective than levodopa, (-)-3-(3,4
dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic
antiparkinson drugs has not yet been established.
Drug-Induced Extrapyramidal Reactions
SYMMETREL is indicated in the treatment of drug-induced extrapyramidal reactions. Although
anticholinergic-type side effects have been noted with SYMMETREL when used in patients with
drug-induced extrapyramidal reactions, there is a lower incidence of these side effects than that
observed with the anticholinergic antiparkinson drugs.
CONTRAINDICATIONS
SYMMETREL is contraindicated in patients with known hypersensitivity to amantadine
hydrochloride or to any of the other ingredients in SYMMETREL.
WARNINGS
Deaths
Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal
dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine.
Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity.
Cardiac dysfunction includes arrhythmia, tachycardia and hypertension (see OVERDOSAGE).
Suicide Attempts
Suicide attempts, some of which have been fatal, have been reported in patients treated with
SYMMETREL, many of whom received short courses for influenza treatment or prophylaxis.
The incidence of suicide attempts is not known and the pathophysiologic mechanism is not
understood. Suicide attempts and suicidal ideation have been reported in patients with and
without prior history of psychiatric illness. SYMMETREL can exacerbate mental problems in
patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide
may exhibit abnormal mental states which include disorientation, confusion, depression,
personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic
reactions, and somnolence or insomnia. Because of the possibility of serious adverse effects,
caution should be observed when prescribing SYMMETREL to patients being treated with drugs
having CNS effects, or for whom the potential risks outweigh the benefit of treatment.
CNS Effects
Patients with a history of epilepsy or other “seizures” should be observed closely for possible
increased seizure activity.
Patients receiving SYMMETREL who note central nervous system effects or blurring of vision
should be cautioned against driving or working in situations where alertness and adequate motor
coordination are important.
5
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Other
Patients with a history of congestive heart failure or peripheral edema should be followed closely
as there are patients who developed congestive heart failure while receiving SYMMETREL.
Patients with Parkinson’s disease improving on SYMMETREL should resume normal activities
gradually and cautiously, consistent with other medical considerations, such as the presence of
osteoporosis or phlebothrombosis.
Because SYMMETREL has anticholinergic effects and may cause mydriasis, it should not be
given to patients with untreated angle closure glaucoma.
PRECAUTIONS
SYMMETREL should not be discontinued abruptly in patients with Parkinson’s disease since a
few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration,
when this medication was suddenly stopped. The dose of anticholinergic drugs or of
SYMMETREL should be reduced if atropine-like effects appear when these drugs are used
concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions,
hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech.
Neuroleptic Malignant Syndrome (NMS)
Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in
association with dose reduction or withdrawal of SYMMETREL therapy. Therefore, patients
should be observed carefully when the dosage of SYMMETREL is reduced abruptly or
discontinued, especially if the patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia;
neurologic findings including muscle rigidity, involuntary movements, altered consciousness;
mental status changes; other disturbances such as autonomic dysfunction, tachycardia,
tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation,
leukocytosis, myoglobinuria, and increased serum myoglobin.
The early diagnosis of this condition is important for the appropriate management of these
patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g.,
pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical
presentation includes both serious medical illness and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central
nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical
monitoring, and 2) treatment of any concomitant serious medical problems for which specific
treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such
as dantrolene are often used in the treatment of NMS, however, their effectiveness has not been
demonstrated in controlled studies.
6
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Renal disease
Because SYMMETREL is mainly excreted in the urine, it accumulates in the plasma and in the
body when renal function declines. Thus, the dose of SYMMETREL should be reduced in
patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE
AND ADMINISTRATION; Dosage for Impaired Renal Function).
Liver disease
Care should be exercised when administering SYMMETREL to patients with liver disease. Rare
instances of reversible elevation of liver enzymes have been reported in patients receiving
SYMMETREL, though a specific relationship between the drug and such changes has not been
established.
Other
The dose of SYMMETREL may need careful adjustment in patients with congestive heart
failure, peripheral edema, or orthostatic hypotension. Care should be exercised when
administering SYMMETREL to patients with a history of recurrent eczematoid rash, or to
patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents.
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or
occur as complications during the course of influenza. SYMMETREL has not been shown to
prevent such complications.
Information for Patients
Patients should be advised of the following information:
Blurry vision and/or impaired mental acuity may occur.
Gradually increase physical activity as the symptoms of Parkinson’s disease improve.
Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as
dizziness, confusion, lightheadedness and orthostatic hypotension.
Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness
occurs, notify physician.
Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or
shortness of breath occur.
Do not take more medication than prescribed because of the risk of overdose. If there is no
improvement in a few days, or if medication appears less effective after a few weeks, discuss
with a physician.
Consult physician before discontinuing medication.
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Seek medical attention immediately if it is suspected that an overdose of medication has been
taken.
Drug Interactions
Careful observation is required when SYMMETREL is administered concurrently with central
nervous system stimulants.
Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of
amantadine.
Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with
Parkinson’s disease, however, it is not known if other phenothiazines produce a similar response.
Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma
amantadine concentration in a 61-year-old man receiving SYMMETREL (Amantadine
Hydrochloride, USP) 100 mg TID for Parkinson’s disease.1 It is not known which of the
components of Dyazide contributed to the observation or if related drugs produce a similar
response.
Coadministration of quinine or quinidine with amantadine was shown to reduce the renal
clearance of amantadine by about 30%.
The concurrent use of SYMMETREL with live attenuated influenza vaccine (LAIV) intranasal
has not been evaluated. However, because of the potential for interference between these
products, LAIV should not be administered within 2 weeks before or 48 hours after
administration of SYMMETREL, unless medically indicated. The concern about possible
interference arises from the potential for antiviral drugs to inhibit replication of live vaccine
virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of
SYMMETREL.
Carcinogenesis and Mutagenesis
Long-term in vivo animal studies designed to evaluate the carcinogenic potential of
SYMMETREL have not been performed. In several in vitro assays for gene mutation,
SYMMETREL did not increase the number of spontaneously observed mutations in four strains
of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary
cells) when incubations were performed either with or without a liver metabolic activation
extract. Further, there was no evidence of chromosome damage observed in an in vitro test using
freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic
activation) or in an in vivo mouse bone marrow micronucleus test (140-550 mg/kg; estimated
human equivalent doses of 11.7-45.8 mg/kg based on body surface area conversion).
Impairment of Fertility
The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted
under Good Laboratory Practice (GLP) and according to current recommended methodology. In
a three litter, non-GLP, reproduction study in rats, Symmetrel at a dose of 32 mg/kg/day (equal
to the maximum recommended human dose on a mg/m2 basis) administered to both males and
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
females slightly impaired fertility. There were no effects on fertility at a dose level of 10
mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m2 basis);
intermediate doses were not tested.
Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor
ingested amantadine 2 weeks prior to, and during the IVF cycle.
Pregnancy Category C
The effect of amantadine on embryofetal and peri-postnatal development has not been
adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and
according to current recommended methodology. However, in two non-GLP studies in rats in
which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7-14 of
gestation, Symmetrel produced increases in embryonic death at an oral dose of 100 mg/kg (or 3
times the maximum recommended human dose on a mg/m2 basis). In the non-GLP rat study in
which females were dosed on Days 7-14 of gestation, there was a marked increase in severe
visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times,
respectively, the maximum recommended human dose on a mg/m2 basis). The no-effect dose for
teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m2
basis). The safety margins reported may not accurately reflect the risk considering the
questionable quality of the study on which they are based. There are no adequate and well-
controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of
amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an
infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days
during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with
pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d)
administered during the first 2 weeks of pregnancy. SYMMETREL should be used during
pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus.
Nursing Mothers
SYMMETREL is excreted in human milk. Use is not recommended in nursing mothers.
Pediatric Use
The safety and efficacy of SYMMETREL in newborn infants and infants below the age of 1 year
have not been established.
Usage in the Elderly
Because SYMMETREL is primarily excreted in the urine, it accumulates in the plasma and in
the body when renal function declines. Thus, the dose of SYMMETREL should be reduced in
patients with renal impairment and in individuals who are 65 years of age or older. The dose of
SYMMETREL may need reduction in patients with congestive heart failure, peripheral edema,
or orthostatic hypotension (see DOSAGE AND ADMINISTRATION).
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
The adverse reactions reported most frequently at the recommended dose of SYMMETREL (5
10%) are: nausea, dizziness (lightheadedness), and insomnia.
Less frequently (1-5%) reported adverse reactions are: depression, anxiety and irritability,
hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral
edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality,
agitation, dry nose, diarrhea and fatigue.
Infrequently (0.1-1%) occurring adverse reactions are: congestive heart failure, psychosis,
urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking
abnormality, amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance,
including punctate subepithelial or other corneal opacity, corneal edema, decreased visual acuity,
sensitivity to light, and optic nerve palsy.
Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia,
neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal
ideation (see WARNINGS).
Other adverse reactions reported during postmarketing experience with SYMMETREL usage
include:
Nervous System/Psychiatric
coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid
reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG
changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions,
hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech;
Cardiovascular
cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia;
Respiratory
acute respiratory failure, pulmonary edema, and tachypnea;
Gastrointestinal
dysphagia;
Hematologic
leukocytosis; agranulocytosis
Special Senses
keratitis and mydriasis;
Skin and Appendages
pruritus and diaphoresis;
Miscellaneous
neuroleptic malignant syndrome (see WARNINGS), allergic reactions including anaphylactic
reactions, edema, and fever;
10
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Laboratory Test
elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and
SGPT.
OVERDOSAGE
Deaths have been reported from overdose with SYMMETREL. The lowest reported acute lethal
dose was 1 gram. Because some patients have attempted suicide by overdosing with amantadine,
prescriptions should be written for the smallest quantity consistent with good patient
management.
Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose
has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction
includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress
(including adult respiratory distress syndrome - ARDS) have been reported; renal dysfunction
including increased BUN, decreased creatinine clearance and renal insufficiency can occur.
Central nervous system effects that have been reported include insomnia, anxiety, agitation,
aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion,
disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy,
somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure
disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.
There is no specific antidote for an overdose of SYMMETREL. However, slowly administered
intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg
doses in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported
to be effective in the control of central nervous system toxicity caused by amantadine
hydrochloride. For acute overdosing, general supportive measures should be employed along
with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary,
given intravenously. The pH of the urine has been reported to influence the excretion rate of
SYMMETREL. Since the excretion rate of SYMMETREL increases rapidly when the urine is
acidic, the administration of urine acidifying drugs may increase the elimination of the drug from
the body. The blood pressure, pulse, respiration and temperature should be monitored. The
patient should be observed for hyperactivity and convulsions; if required, sedation, and
anticonvulsant therapy should be administered. The patient should be observed for the possible
development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and
antihypotensive therapy should be given. Electrocardiographic monitoring may be required after
ingestion, since malignant tachyarrhythmias can appear after overdose.
Care should be exercised when administering adrenergic agents, such as isoproterenol, to
patients with a SYMMETREL overdose, since the dopaminergic activity of SYMMETREL has
been reported to induce malignant arrhythmias.
The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of
recent voiding, catheterization should be done.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
The dose of SYMMETREL (Amantadine Hydrochloride, USP) may need reduction in patients
with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal
function (see Dosage for Impaired Renal Function).
Dosage for Prophylaxis and Treatment of Uncomplicated Influenza A Virus Illness
Adult
The adult daily dosage of SYMMETREL is 200 mg; two 100 mg tablets (or four teaspoonfuls of
syrup) as a single daily dose. The daily dosage may be split into one tablet of 100 mg (or two
teaspoonfuls of syrup) twice a day. If central nervous system effects develop in once-a-day
dosage, a split dosage schedule may reduce such complaints. In persons 65 years of age or older,
the daily dosage of SYMMETREL is 100 mg.
A 100 mg daily dose has also been shown in experimental challenge studies to be effective as
prophylaxis in healthy adults who are not at high risk for influenza-related complications.
However, it has not been demonstrated that a 100 mg daily dose is as effective as a 200 mg daily
dose for prophylaxis, nor has the 100 mg daily dose been studied in the treatment of acute
influenza illness. In recent clinical trials, the incidence of central nervous system (CNS) side
effects associated with the 100 mg daily dose was at or near the level of placebo. The 100 mg
dose is recommended for persons who have demonstrated intolerance to 200 mg of
SYMMETREL daily because of CNS or other toxicities.
Pediatric Patients: 1 yr.-9 yrs. of age
The total daily dose should be calculated on the basis of 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day),
but not to exceed 150 mg per day.
9 yrs.-12 yrs. of age
The total daily dose is 200 mg given as one tablet of 100 mg (or two teaspoonfuls of syrup) twice
a day. The 100 mg daily dose has not been studied in this pediatric population. Therefore, there
are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily
dose in this patient population.
Prophylactic dosing should be started in anticipation of an influenza A outbreak and before or
after contact with individuals with influenza A virus respiratory tract illness.
SYMMETREL should be continued daily for at least 10 days following a known exposure. If
SYMMETREL is used chemoprophylactically in conjunction with inactivated influenza A virus
vaccine until protective antibody responses develop, then it should be administered for 2 to 4
weeks after the vaccine has been given. When inactivated influenza A virus vaccine is
unavailable or contraindicated, SYMMETREL should be administered for the duration of known
influenza A in the community because of repeated and unknown exposure.
Treatment of influenza A virus illness should be started as soon as possible, preferably within 24
to 48 hours after onset of signs and symptoms, and should be continued for 24 to 48 hours after
the disappearance of signs and symptoms.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosage for Parkinsonism
Adult
The usual dose of SYMMETREL is 100 mg twice a day when used alone. SYMMETREL has an
onset of action usually within 48 hours.
The initial dose of SYMMETREL is 100 mg daily for patients with serious associated medical
illnesses or who are receiving high doses of other antiparkinson drugs. After one to several
weeks at 100 mg once daily, the dose may be increased to 100 mg twice daily, if necessary.
Occasionally, patients whose responses are not optimal with SYMMETREL at 200 mg daily may
benefit from an increase up to 400 mg daily in divided doses. However, such patients should be
supervised closely by their physicians.
Patients initially deriving benefit from SYMMETREL not uncommonly experience a fall-off of
effectiveness after a few months. Benefit may be regained by increasing the dose to 300 mg
daily. Alternatively, temporary discontinuation of SYMMETREL for several weeks, followed by
reinitiation of the drug, may result in regaining benefit in some patients. A decision to use other
antiparkinson drugs may be necessary.
Dosage for Concomitant Therapy
Some patients who do not respond to anticholinergic antiparkinson drugs may respond to
SYMMETREL. When SYMMETREL or anticholinergic antiparkinson drugs are each used with
marginal benefit, concomitant use may produce additional benefit.
When SYMMETREL and levodopa are initiated concurrently, the patient can exhibit rapid
therapeutic benefits. SYMMETREL should be held constant at 100 mg daily or twice daily while
the daily dose of levodopa is gradually increased to optimal benefit.
When SYMMETREL is added to optimal well-tolerated doses of levodopa, additional benefit
may result, including smoothing out the fluctuations in improvement which sometimes occur in
patients on levodopa alone. Patients who require a reduction in their usual dose of levodopa
because of development of side effects may possibly regain lost benefit with the addition of
SYMMETREL.
Dosage for Drug-Induced Extrapyramidal Reactions
Adult
The usual dose of SYMMETREL is 100 mg twice a day. Occasionally, patients whose responses
are not optimal with SYMMETREL at 200 mg daily may benefit from an increase up to 300 mg
daily in divided doses.
Dosage for Impaired Renal Function
Depending upon creatinine clearance, the following dosage adjustments are recommended:
13
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CREATININE
SYMMETREL
CLEARANCE
DOSAGE
(mL/min/1.73m2)
30-50
200 mg 1st day and 100 mg
each day thereafter
15-29
200 mg 1st day followed by
100 mg on alternate days
<15
200 mg every 7 days
The recommended dosage for patients on hemodialysis is 200 mg every 7 days.
HOW SUPPLIED
SYMMETREL (Amantadine Hydrochloride, USP) is available in light orange, convex curved,
triangular shaped 100 mg tablets with “SYMMETREL” debossed on one side and plain on the
other side as follows:
Bottles of 100
NDC 63481-108-70
As a clear, colorless syrup [each 5 mL (1 teaspoonful) contains 50 mg amantadine
hydrochloride] in:
16 oz. (480 mL) bottles
NDC 63481-205-16
Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room
Temperature].
Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).
REFERENCES
1W.W. Wilson and A.H. Rajput, Amantadine-Dyazide Interaction, Can. Med. Assoc. J. 129:974
975, 1983.
2D.F. Casey, N. Engl. J. Med. 298:516, 1978.
3C.D. Berkowitz, J. Pediatr. 95:144, 1979.
Manufactured for:
Endo Pharmaceuticals Inc. logo
Chadds Ford, PA 19317
SYMMETREL® is a Registered Trademark of Endo Pharmaceuticals Inc.
Copyright © Endo Pharmaceuticals Inc. 2008
Printed in U.S.A.
2008806/August, 2008
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:37.072088
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/016023s040,018101s015lbl.pdf', 'application_number': 18101, 'submission_type': 'SUPPL ', 'submission_number': 15}
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11,166
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Azmacort
Azmacort
Azmacort
Azmacort®®®®
(triamcinolone acetonide)
(triamcinolone acetonide)
(triamcinolone acetonide)
(triamcinolone acetonide)
Inhalation Aerosol
Inhalation Aerosol
Inhalation Aerosol
Inhalation Aerosol
Rx Only
Rx Only
Rx Only
Rx Only
For Oral Inhalation Only
For Oral Inhalation Only
For Oral Inhalation Only
For Oral Inhalation Only
Shake Well Before Using
Shake Well Before Using
Shake Well Before Using
Shake Well Before Using
DESCRIPTION
DESCRIPTION
DESCRIPTION
DESCRIPTION
Proprietary name:
Proprietary name:
Proprietary name:
Proprietary name:
Azmacort
Established name:
Established name:
Established name:
Established name:
Triamcinolone acetonide
Route of administration:
Route of administration:
Route of administration:
Route of administration:
RESPIRATORY (INHALATION) (C38216)
Active ingredients (moiety):
Active ingredients (moiety):
Active ingredients (moiety):
Active ingredients (moiety):
Triamcinolone acetonide (Triamcinolone)
####
Strength
Strength
Strength
Strength
Form
Form
Form
Form
Inactive ingredients
Inactive ingredients
Inactive ingredients
Inactive ingredients
1
60 MILLIGRAM
AEROSOL, METERED (C42960)
Dehydrated alcohol, dichlorodifluoromethane
Triamcinolone acetonide, USP, the active ingredient in Azmacort
Azmacort
Azmacort
Azmacort® Inhalation Aerosol, is a
corticosteroid with a molecular weight of 434.5 and with the chemical designation 9-
Fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with
acetone. (C24H31FO6).
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol is a metered-dose aerosol unit containing a microcrystalline
suspension of triamcinolone acetonide in the propellant dichlorodifluoromethane and
dehydrated alcohol USP 1% w/w. Each canister contains 60 mg triamcinolone acetonide.
The canister must be primed prior to the first use. After an initial priming of 2 actuations,
each actuation delivers 200 mcg triamcinolone acetonide from the valve and 75 mcg from
the spacer-mouthpiece under defined in vitro test conditions. The canister will remain
primed for 3 days. If the canister is not used for more than 3 days, then it should be
reprimed with 2 actuations. There are at least 240 actuations in one Azmacort
Azmacort
Azmacort
Azmacort Inhalation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Aerosol canister. After 240 actuations, the amount delivered per actuation may not be
After 240 actuations, the amount delivered per actuation may not be
After 240 actuations, the amount delivered per actuation may not be
After 240 actuations, the amount delivered per actuation may not be
consistent and the unit should be discarded.
consistent and the unit should be discarded.
consistent and the unit should be discarded.
consistent and the unit should be discarded.
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
Triamcinolone acetonide is a more potent derivative of triamcinolone. Although
triamcinolone itself is approximately one to two times as potent as prednisone in animal
models of inflammation, triamcinolone acetonide is approximately 8 times more potent
than prednisone.
The precise mechanism of the action of glucocorticoids in asthma is unknown. However,
the inhaled route makes it possible to provide effective local anti-inflammatory activity with
reduced systemic corticosteroid effects. Though highly effective for asthma,
glucocorticoids do not affect asthma symptoms immediately. While improvement in
asthma may occur as soon as one week after initiation of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol
therapy, maximum improvement may not be achieved for 2 weeks or longer.
Based upon intravenous dosing of triamcinolone acetonide phosphate ester, the half-life of
triamcinolone acetonide was reported to be 88 minutes. The volume of distribution (Vd)
reported was 99.5 L (SD ± 27.5) and clearance was 45.2 L/hour (SD ± 9.1) for
triamcinolone acetonide. The plasma half-life of glucocorticoids does not correlate well
with the biologic half-life.
The pharmacokinetics of radiolabeled triamcinolone acetonide [14C] were evaluated
following a single oral dose of 800 mcg to healthy male volunteers. Radiolabeled
triamcinolone acetonide was found to undergo relatively rapid absorption following oral
administration with maximum plasma triamcinolone acetonide and [14C]-derived
radioactivity occurring between 1.5 and 2 hours. Plasma protein binding of triamcinolone
acetonide appears to be relatively low and consistent over a wide plasma triamcinolone
acetonide concentration range as a function of time. The overall mean percent fraction
bound was approximately 68%.
The metabolism and excretion of triamcinolone acetonide were both rapid and extensive
with no parent compound being detected in the plasma after 24 hours post-dose and a low
ratio (10.6%) of parent compound AUC0-∞ to total [14C] radioactivity AUC0-∞. Greater than
90% of the oral [14C]-radioactive dose was recovered within 5 days after administration in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 out of the 6 subjects in the study. Of the recovered [14C]-radioactivity, approximately
40% and 60% were found in the urine and feces, respectively.
Three metabolites of triamcinolone acetonide have been identified. They are 6β-
hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6β-
hydroxytriamcinolone acetonide. All three metabolites are expected to be substantially
less active than the parent compound due to (a) the dependence of anti-inflammatory
activity on the presence of a 21-hydroxyl group, (b) the decreased activity observed upon
6-hydroxylation, and (c) the markedly increased water solubility favoring rapid elimination.
There appeared to be some quantitative differences in the metabolites among species. No
differences were detected in metabolic pattern as a function of route of administration.
CLINICAL TRIALS
CLINICAL TRIALS
CLINICAL TRIALS
CLINICAL TRIALS
Double-blind, placebo-controlled efficacy and safety studies have been conducted in
asthma patients with a range of asthma severities, from those patients with mild disease
to those with severe disease requiring oral steroid therapy.
The efficacy and safety of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol given twice daily was
demonstrated in two placebo-controlled clinical trials. In two separate studies, 222
asthmatic patients were randomized to receive either Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol 300
mcg twice daily or matching placebo for a treatment period of 6 weeks. Patients were
adult asthmatics who were using inhaled beta2-agonists on more than an occasional basis
(at least three times weekly), either without or with inhaled corticosteroids, for control of
their asthma symptoms. For the combined studies, 48% (52/109) patients randomized to
placebo and 41% (46/113) patients randomized to Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol treatment
were previously treated with inhaled corticosteroids.
Results of weekly lung function tests (FEV1) from one of these trials is presented
graphically below. Results of the second study are presented in tabular form as the
changes in asthma measures from baseline to the end of the treatment period.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Mean Changes in Asthma Measures from Baseline to Endpoint
Mean Changes in Asthma Measures from Baseline to Endpoint
Mean Changes in Asthma Measures from Baseline to Endpoint
Mean Changes in Asthma Measures from Baseline to Endpointaaaa All
All
All
All----Treated Patients Results from a
Treated Patients Results from a
Treated Patients Results from a
Treated Patients Results from a
Placebo
Placebo
Placebo
Placebo----Controlled, 6 Week Study
Controlled, 6 Week Study
Controlled, 6 Week Study
Controlled, 6 Week Study
Asthma Measure
Asthma Measure
Asthma Measure
Asthma Measure
Placebo
Placebo
Placebo
Placebo
(N=61)
(N=61)
(N=61)
(N=61)
Azmacort 300 mcg bid
Azmacort 300 mcg bid
Azmacort 300 mcg bid
Azmacort 300 mcg bid
(N=60)
(N=60)
(N=60)
(N=60)
Percent Change in FEV1(%)
2.8%
17.5%
Increase in Morning Peak
Flow Rate (L/min)
6.7
45.9
Decrease in Albuterol Use
(puffs/day)
0.6
3.4
Decrease in Daily Asthma Symptom Score (units/day)b
0.5
2.3
aEndpoint results are obtained from the last evaluable data, regardless of whether the patient completed 6 weeks of
treatment
bScale (0-6) with 0 = no symptom: Maximum Score (AM + PM) =12
In both studies, treatment with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol (300 mcg twice daily) resulted
in significant improvements in all clinical asthma measures (lung functions, asthma
symptoms, use of as-needed beta2-agonist medications) when compared to placebo.
INDICATIONS
INDICATIONS
INDICATIONS
INDICATIONS
Azmacort Inhalation Aerosol is indicated in the maintenance treatment of asthma as
prophylactic therapy. Azmacort Inhalation Aerosol is also indicated for asthma patients
who require systemic corticosteroid administration, where adding Azmacort may reduce or
eliminate the need for the systemic corticosteroids.
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol is NOT indicated for the relief of acute bronchospasm.
CONTRAINDICATIONS
CONTRAINDICATIONS
CONTRAINDICATIONS
CONTRAINDICATIONS
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol is contraindicated in the primary treatment of status
asthmaticus or other acute episodes of asthma where intensive measures are required.
Hypersensitivity to triamcinolone acetonide or any of the other ingredients in this
preparation contraindicates its use.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
WARNINGS
WARNINGS
WARNINGS
Particular care is needed in patients who are transferred from systemically active
corticosteroids to Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol because deaths due to adrenal
insufficiency have occurred in asthmatic patients during and after transfer from systemic
corticosteroids to aerosolized steroids in recommended doses. After withdrawal from
systemic corticosteroids, a number of months is usually required for recovery of
hypothalamic-pituitary-adrenal (HPA) function. For some patients who have received large
doses of oral steroids for long periods of time before therapy with Azmacort
Azmacort
Azmacort
Azmacort Inhalation
Aerosol is initiated, recovery may be delayed for one year or longer. During this period of
HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when
exposed to trauma, surgery, or infections, particularly gastroenteritis or other conditions
with acute electrolyte loss. Although Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol may provide control of
asthmatic symptoms during these episodes, in recommended doses it supplies only
normal physiological amounts of corticosteroid systemically and does NOT provide the
increased systemic steroid which is necessary for coping with these emergencies.
During periods of stress or a severe asthmatic attack, patients who have been recently
withdrawn from systemic corticosteroids should be instructed to resume systemic steroids
(in large doses) immediately and to contact their physician for further instruction. These
patients should also be instructed to carry a warning card indicating that they may need
supplementary systemic steroids during periods of stress or a severe asthma attack.
Localized infections with Candida albicans have occurred infrequently in the mouth and
pharynx. These areas should be examined by the treating physician at each patient visit.
The percentage of positive mouth and throat cultures for Candida albicans did not change
during a year of continuous therapy. The incidence of clinically apparent infection is low
(2.5%). These infections may disappear spontaneously or may require treatment with
appropriate antifungal therapy or discontinuance of treatment with Azmacort
Azmacort
Azmacort
Azmacort Inhalation
Aerosol.
Children who are on immunosuppressant drugs are more susceptible to infections than
healthy children. Chickenpox and measles, for example, can have a more serious or even
fatal course in children on immunosuppressant doses of corticosteroids. In such children,
or in adults who have not had these diseases, particular care should be taken to avoid
exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chickenpox
develops, treatment with antiviral agents may be considered.
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol is not to be regarded as a bronchodilator and is not indicated
for rapid relief of bronchospasm.
As with other inhaled asthma medications, bronchospasm may occur with an immediate
increase in wheezing following dosing. If bronchospasm occurs following use of Azmacort
Azmacort
Azmacort
Azmacort
Inhalation Aerosol, it should be treated immediately with a fast-acting inhaled
bronchodilator. Treatment with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol should be discontinued and
alternative treatment should be instituted.
Patients should be instructed to contact their physician immediately when episodes of
asthma which are not responsive to bronchodilators occur during the course of treatment
with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol. During such episodes, patients may require therapy
with systemic corticosteroids.
The use of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol with systemic prednisone, dosed either daily or on
alternate days, could increase the likelihood of HPA suppression compared to a
therapeutic dose of either one alone. Therefore, Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol should be
used with caution in patients already receiving prednisone treatment for any disease.
Transfer of patients from systemic steroid therapy to Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol may
unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g.,
rhinitis, conjunctivitis, and eczema.
PRECAUTIONS
PRECAUTIONS
PRECAUTIONS
PRECAUTIONS
Orally inhaled corticosteroids may cause a reduction in growth velocity when administered
to pediatric patients (see PRECAUTIONS, Pediatric Use
PRECAUTIONS, Pediatric Use
PRECAUTIONS, Pediatric Use
PRECAUTIONS, Pediatric Use). Because of the possibility of
systemic absorption of inhaled corticosteroids, patients treated with these drugs should be
observed carefully for any evidence of systemic corticosteroid effects including
suppression of growth in children. Particular care should be taken in observing patients
postoperatively or during periods of stress for evidence of a decrease in adrenal function.
During withdrawal from oral steroids, some patients may experience symptoms of
systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude, and
depression, despite maintenance or even improvement of respiratory function. (See
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION.) Although steroid withdrawal effects are usually
transient and not severe, severe and even fatal exacerbation of asthma can occur if the
previous daily oral corticosteroid requirement had significantly exceeded 10 mg/day of
prednisone or equivalent.
In responsive patients, inhaled corticosteroids will often permit control of asthmatic
symptoms with less suppression of HPA function than therapeutically equivalent oral
doses of prednisone. Since triamcinolone acetonide is absorbed into the circulation and
can be systemically active, the beneficial effects of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol in
minimizing or preventing HPA dysfunction may be expected only when recommended
dosages are not exceeded.
Suppression of HPA function has been reported in volunteers who received 4000 mcg
daily of triamcinolone acetonide by oral inhalation. In addition, suppression of HPA
function has been reported in some patients who have received recommended doses for
as little as 6 to 12 weeks. Since the response of HPA function to inhaled corticosteroids is
highly individualized, the physician should consider this information when treating patients.
When used at excessive doses or at recommended doses in a small number of
susceptible individuals, systemic corticosteroid effects such as hypercorticoidism and
adrenal suppression may appear. If such changes occur, Azmacort
Azmacort
Azmacort
Azmacort ® Inhalation Aerosol
should be discontinued slowly, consistent with accepted procedures for reducing systemic
steroid therapy and for management of asthma symptoms.
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol should be used with caution, if at all, in patients with active or
quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal,
bacterial, parasitic, or viral infections; or ocular herpes simplex.
The long-term local and systemic effects of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol in human
subjects are still not fully known. While there has been no clinical evidence of adverse
experiences, the effects resulting from chronic use of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol on
developmental or immunologic processes in the mouth, pharynx, trachea, and lung are
unknown.
Information for Patients:
Information for Patients:
Information for Patients:
Information for Patients: Patients being treated with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol should
receive the following information and instructions. This information is intended to aid them
in the safe and effective use of this medication. It is not a complete disclosure of all
possible adverse or intended effects.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should use Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol at regular intervals as directed. Results
of clinical trials indicate that significant improvement in asthma may occur by 1 week, but
maximum benefit may not be achieved for 2 weeks or more. The patient should not
increase the prescribed dosage but should contact the physician if symptoms do not
improve or if the condition worsens.
In clinical studies and post-marketing experience with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol, local
infections of the oropharynx with Candida albicans have occurred. When such an infection
develops, it should be treated with appropriate local or systemic (i.e., oral antifungal)
therapy while remaining on treatment with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol. However, at times
therapy with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol may need to be interrupted.
Patients should be instructed to track their use of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol and to
dispose of the canister after 240 actuations since reliable dose delivery cannot be assured
after 240 doses.
Patients who are on immunosuppressant doses of corticosteroids should be warned to
avoid exposure to chickenpox or measles and, if exposed, to obtain medical advice.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of treatment-related
carcinogenicity was demonstrated after two years of once daily gavage of triamcinolone
acetonide at doses of 0.05, 0.2, and 1.0 mcg/kg (approximately 0.02, 0.07, and 0.4% of
the maximum recommended human daily inhalation dose on a mcg/m2 basis) in the rat
and 0.1, 0.6, and 3.0 mcg/kg (approximately 0.02, 0.1, and 0.6% of the maximum
recommended human daily inhalation dose on a mcg/m2 basis) in a mouse.
Mutagenesis studies with triamcinolone acetonide have not been carried out.
No evidence of impaired fertility was manifested when oral doses of up to 15.0 mcg/kg
(8% of the maximum recommended human daily inhalation dose on a mcg/m2 basis) were
administered to female and male rats. However, triamcinolone acetonide at oral doses of
8 mcg/kg (approximately 4% of the maximum recommended human daily inhalation dose
on a mcg/m2 basis) caused dystocia and prolonged delivery and at oral doses of 5.0
mcg/kg (approximately 2.5% of the maximum recommended human daily inhalation dose
on a mcg/m2 basis) and above caused increases in fetal resorptions and stillbirths and
decreases in pup body weight and survival. At a lower dose of 1.0 mcg/kg (approximately
0.5% of the maximum recommended human daily inhalation dose on a mcg/m2 basis) it
did not induce the above mentioned effects.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy:
Pregnancy:
Pregnancy:
Pregnancy: Pregnancy Category C. Triamcinolone acetonide has been shown to be
teratogenic at inhalational doses of 20, 40, and 80 mcg/kg in rats (approximately 0.1, 0.2,
and 0.4 times the maximum recommended human daily inhalation dose on a mcg/m2
basis, respectively), in rabbits at the same doses (approximately 0.2, 0.4, and 0.8 times
the maximum recommended human daily inhalation dose on a mcg/m2 basis,
respectively) and in monkeys, at an inhalational dose of 500 mcg/kg (approximately 5
times the maximum recommended human daily inhalation dose on a mcg/m2 basis). Dose
related teratogenic effects in rats and rabbits included cleft palate and/or internal
hydrocephaly and axial skeletal defects whereas the teratogenic effects observed in the
monkey were CNS and/or cranial malformations. There are no adequate and well
controlled studies in pregnant women. Triamcinolone acetonide should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Experience with oral glucocorticoids since their introduction in pharmacologic as opposed
to physiologic doses suggests that rodents are more prone to teratogenic effects from
glucocorticoids than humans. In addition, because there is a natural increase in
glucocorticoid production during pregnancy, most women will require a lower exogenous
steroid dose and many will not need glucocorticoid treatment during pregnancy.
Nonteratogenic Effe
Nonteratogenic Effe
Nonteratogenic Effe
Nonteratogenic Effects:
cts:
cts:
cts: Hypoadrenalism may occur in infants born of mothers receiving
corticosteroids during pregnancy. Such infants should be carefully observed.
Nursing Mothers:
Nursing Mothers:
Nursing Mothers:
Nursing Mothers: It is not known whether triamcinolone acetonide is excreted in human
milk. Because other corticosteroids are excreted in human milk, caution should be
exercised when Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol is administered to nursing women.
Pediatric Use:
Pediatric Use:
Pediatric Use:
Pediatric Use: Safety and effectiveness have not been established in pediatric patients
below the age of 6.
Controlled clinical studies have shown that orally inhaled corticosteroids may cause a
reduction in growth velocity in pediatric patients. In these studies, the mean reduction in
growth velocity was approximately one centimeter (cm) per year (range 0.3 to 1.8 cm per
year; 0.12 to 0.71 inches) and appears to depend upon dose and duration of exposure.
[The specific growth effects of Azmacort
Azmacort
Azmacort
Azmacort have also been studied in a controlled clinical trial
(see data below)]. This effect was observed in the absence of laboratory evidence of
hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than
some commonly used tests of HPA axis function.
To assess if Azmacor
Azmacor
Azmacor
Azmacortttt has an effect on growth, a one-year, randomized, open-label study
of pre-pubescent boys and girls ages 6-11 with moderate to severe asthma was
conducted. Children with moderate asthma were randomized to a nonsteroidal treatment
or to Azmacort
Azmacort
Azmacort
Azmacort, children with severe asthma to Azmacort
Azmacort
Azmacort
Azmacort plus prednisone or just
prednisone alone. A sex and age matched group of healthy non-asthmatic children was
also included. The average daily dose of Azmacort
Azmacort
Azmacort
Azmacort was 400 mcg (range 75 to 1600
mcg/day, dose adjustments were permitted). Non-asthmatic children (mean 8.2 years)
grew 5.93 cm/year (n=96). In the moderate asthma groups, the Azmacort
Azmacort
Azmacort
Azmacort children (mean
8.2 years) grew 5.34 cm/year (n=101) and the nonsteroidal children (mean 8.5 years)
grew 6.13 cm/year (n=95). In the severe groups, the Azmacort
Azmacort
Azmacort
Azmacort plus prednisone children
(mean 8.2 years) grew 5.46 cm/year (n=33) and the prednisone only children (mean 8.0
years) grew 5.59 cm/year (n=31). Due to low enrollment in the severe patient groups,
there was insufficient power to interpret the statistical analyses on these groups.
The long-term effects of this reduction in growth velocity associated with orally inhaled
corticosteroids, including the impact on final adult height, are unknown. The potential for
“catch up” growth following discontinuation of treatment with orally inhaled corticosteroids
has not been adequately studied. The growth of children and adolescents receiving orally
inhaled corticosteroids, including Azmacort
Azmacort
Azmacort
Azmacort, should be monitored routinely (e.g. via
stadiometry). The potential growth effects of prolonged treatment should be weighed
against the clinical benefits obtained and the risk associated with alternative therapies. To
minimize the systemic effects of orally inhaled corticosteroids, including Azmacort
Azmacort
Azmacort
Azmacort , each
patient should be titrated to the lowest dose that effectively controls his/her symptoms.
Geriatric Use:
Geriatric Use:
Geriatric Use:
Geriatric Use: Clinical studies of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
ADVERSE REACTIONS
ADVERSE REACTIONS
ADVERSE REACTIONS
ADVERSE REACTIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The table below describes the incidence of common adverse experiences based upon
three placebo-controlled, multicenter US clinical trials of 507 patients (297 female and 210
male adults (age range 18-64)). These trials included asthma patients who had previously
received inhaled beta2-agonists alone, as well as those who previously required inhaled
corticosteroid therapy for the control of their asthma. The patients were treated with
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol (including doses ranging from 150 to 600 mcg twice daily for
6 weeks) or placebo.
Adverse Events Occurring at an Incidence of Greater Th
Adverse Events Occurring at an Incidence of Greater Th
Adverse Events Occurring at an Incidence of Greater Th
Adverse Events Occurring at an Incidence of Greater Than 3% and Greater Than Placebo
an 3% and Greater Than Placebo
an 3% and Greater Than Placebo
an 3% and Greater Than Placebo
Adverse Event
Adverse Event
Adverse Event
Adverse Event
Azmacort Dose
Azmacort Dose
Azmacort Dose
Azmacort Dose
Placebo
Placebo
Placebo
Placebo
150 mcg
150 mcg
150 mcg
150 mcg
bid
bid
bid
bid
(n=57)
(n=57)
(n=57)
(n=57)
300 mcg bid
300 mcg bid
300 mcg bid
300 mcg bid
(n=170)
(n=170)
(n=170)
(n=170)
600 mcg
600 mcg
600 mcg
600 mcg
bid
bid
bid
bid
(n=57)
(n=57)
(n=57)
(n=57)
(n=167)
(n=167)
(n=167)
(n=167)
Sinusitis
5 (9%)
7 (4%)
1 (2%)
6 (4%)
Pharyngitis
4 (7%)
42 (25%)
10 (18%)
19 (11%)
Headache
4 (7%)
35 (21%)
7 (12%)
24 (14%)
Flu Syndrome
2 (4%)
8 (5%)
1 (2%)
5 (3%)
Back Pain
2 (4%)
3 (2%)
2 (4%)
3 (2%)
Adverse events that occurred at an incidence of 1-3% in the overall Azmacort
Azmacort
Azmacort
Azmacort Inhalation
Aerosol treatment group and greater than placebo included:
Body as a whole:
Body as a whole:
Body as a whole:
Body as a whole: facial edema, pain, abdominal pain, photosensitivity
Digestive system:
Digestive system:
Digestive system:
Digestive system: diarrhea, oral monilia, toothache, vomiting
Metabolic and Nutrition:
Metabolic and Nutrition:
Metabolic and Nutrition:
Metabolic and Nutrition: weight gain
Musculoskeletal system:
Musculoskeletal system:
Musculoskeletal system:
Musculoskeletal system: bursitis, myalgia, tenosynovitis
Nervous s
Nervous s
Nervous s
Nervous system:
ystem:
ystem:
ystem: dry mouth
Organs of special sense:
Organs of special sense:
Organs of special sense:
Organs of special sense: rash
Respiratory system:
Respiratory system:
Respiratory system:
Respiratory system: chest congestion, voice alteration
Urogenital system:
Urogenital system:
Urogenital system:
Urogenital system: cystitis, urinary tract infection, vaginal monilia
In older controlled clinical trials of steroid dependent asthmatics, urticaria was reported
rarely. Anaphylaxis was not reported in these controlled trials. Typical steroid withdrawal
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
effects including muscle aches, joint aches, and fatigue were noted in clinical trials when
patients were transferred from oral steroid therapy to Azmac
Azmac
Azmac
Azmacort
ort
ort
ort Inhalation Aerosol. Easy
bruisability was also noted in these trials.
Hoarseness, dry throat, irritated throat, dry mouth, facial edema, increased wheezing, and
cough have been reported. These adverse effects have generally been mild and transient.
Cases of oral candidiasis occurring with clinical use have been reported. (See
WARNINGS
WARNINGS
WARNINGS
WARNINGS. . . . ) Cases of growth suppression have been reported for orally inhaled
corticosteroids (see PRECAUTIONS, Pe
PRECAUTIONS, Pe
PRECAUTIONS, Pe
PRECAUTIONS, Pediatric Use section
diatric Use section
diatric Use section
diatric Use section).
Post Marketing:
Post Marketing:
Post Marketing:
Post Marketing: In addition to adverse events reported from clinical trials, the following
events have been identified during post approval use of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol
where these events were reported voluntarily from a population of unknown size, and the
frequency of occurrence cannot be determined precisely. These include rare reports of
anaphylaxis, cataracts, glaucoma and very rare reports of bone mineral density loss and
osteoporosis, especially with prolonged use, which may lead to an increased risk of
fractures.
OVERDOSAGE
OVERDOSAGE
OVERDOSAGE
OVERDOSAGE
There are no data available on the effects of acute or chronic overdose. However, acute
overdosing with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol is unlikely in view of the total amount of
active ingredient present and the route of administration. The maximum total daily dose
(1200 mcg) has been well tolerated when administered as a single dose of 16 consecutive
inhalations to adult asthmatics in a controlled clinical trial. Chronic overdosage may result
in signs/symptoms of hypercorticoidism. (See PRECAUTIONS
PRECAUTIONS
PRECAUTIONS
PRECAUTIONS. . . . ) The risk of candidiasis
could also be increased.
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION
DOSAGE AND ADMINISTRATION
Adults:
Adults:
Adults:
Adults: The usual recommended dosage is two inhalations (150 mcg) given three to four
times a day or four inhalations (300 mcg) given twice daily. The maximal daily intake
should not exceed 16 inhalations (1200 mcg) in adults. Higher initial doses (12 to 16
inhalations per day) may be considered in patients with more severe asthma.
Children 6 to 12 Y
Children 6 to 12 Y
Children 6 to 12 Y
Children 6 to 12 Years of Age:
ears of Age:
ears of Age:
ears of Age: The usual recommended dosage is one or two inhalations
(75 to 150 mcg) given three to four times a day or two to four inhalations (150 to 300 mcg)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
given twice daily. The maximal daily intake should not exceed 12 inhalations (900 mcg) in
children 6 to 12 years of age. Insufficient clinical data exist with respect to the safety and
efficacy of the administration of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol to children below the age of
6. The long-term effects of inhaled steroids, including Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol, on
growth are still not fully known.
Rinsing the mouth after inhalation is advised.
Different considerations must be given to the following groups of patients in order to obtain
the full therapeutic benefit of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol:
Note
Note
Note
Note :::: In all patients, it is desirable to titrate to the lowest effective dose once asthma
In all patients, it is desirable to titrate to the lowest effective dose once asthma
In all patients, it is desirable to titrate to the lowest effective dose once asthma
In all patients, it is desirable to titrate to the lowest effective dose once asthma
stability has been achieved.
stability has been achieved.
stability has been achieved.
stability has been achieved.
Patients Not Receiving Systemic Corticosteroids:
Patients Not Receiving Systemic Corticosteroids:
Patients Not Receiving Systemic Corticosteroids:
Patients Not Receiving Systemic Corticosteroids: Patients who require maintenance
therapy of their asthma may benefit from treatment with Az
Az
Az
Azmacort
macort
macort
macort Inhalation Aerosol at
the doses recommended above. In patients who respond to Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol,
improvement in pulmonary function is usually apparent within one to two weeks after the
initiation of therapy.
Patients Maintained on Systemi
Patients Maintained on Systemi
Patients Maintained on Systemi
Patients Maintained on Systemic Corticosteroids:
c Corticosteroids:
c Corticosteroids:
c Corticosteroids: Clinical studies have shown that
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol may be effective in the management of asthmatics
dependent or maintained on systemic corticosteroids and may permit replacement or
significant reduction in the dosage of systemic corticosteroids.
The patient's asthma should be reasonably stable before treatment with Azmacort
Azmacort
Azmacort
Azmacort
Inhalation Aerosol is started. Initially, Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol should be used
concurrently with the patient's usual maintenance dose of systemic corticosteroid. After
approximately one week, gradual withdrawal of the systemic corticosteroid is started by
reducing the daily or alternate daily dose. Reductions may be made after an interval of
one or two weeks, depending on the response of the patient. A slow rate of withdrawal is
strongly recommended. Generally, these decrements should not exceed 2.5 mg of
prednisone or its equivalent. During withdrawal, some patients may experience symptoms
of systemic corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and
depression, despite maintenance or even improvement in pulmonary function. Such
patients should be encouraged to continue with the inhaler but should be monitored for
objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the
systemic corticosteroid doses should be increased temporarily and thereafter withdrawal
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
should continue more slowly. Inhaled corticosteroids should be used with caution when
used chronically in patients receiving prednisone regimens, either daily or alternate day.
(See WARNINGS
WARNINGS
WARNINGS
WARNINGS. . . . )
During periods of stress or a severe asthma attack, transfer patients may require
supplementary treatment with systemic corticosteroids.
Directions for Use:
Directions for Use:
Directions for Use:
Directions for Use: An illustrated leaflet of patient instructions for proper use accompanies
each package of Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol.
HOW SUPPLIED
HOW SUPPLIED
HOW SUPPLIED
HOW SUPPLIED
####
Name
Name
Name
Name
Strength
Strength
Strength
Strength
Dosage Form
Dosage Form
Dosage Form
Dosage Form
Appearance
Appearance
Appearance
Appearance
Package
Package
Package
Package
Type
Type
Type
Type
Package Qty
Package Qty
Package Qty
Package Qty
NDC
NDC
NDC
NDC
1
Azmacort
60 MILLIGRAM
AEROSOL,
METERED (C42960)
INHALER
(C16738)
60 MILLIGRAM
60598-
061-60
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol contains 60 mg triamcinolone acetonide in a 20 gram
package which delivers at least 240 actuations. It is supplied with a white plastic actuator,
a white plastic spacer-mouthpiece and patient's leaflet of instructions: box of one. NDC
60598-061-60. Each actuation delivers 200 mcg triamcinolone acetonide from the valve
and 75 mcg from the spacer-mouthpiece under defined in vitro test conditions.
Avoid spraying in eyes.
For best results, the canister should be at room temperature before use.
Shake well before using.
CONTENTS UNDER PRESSURE.
CONTENTS UNDER PRESSURE.
CONTENTS UNDER PRESSURE.
CONTENTS UNDER PRESSURE. Do not puncture. Do not use or store near heat or
open flame. Exposure to temperatures above 120°F may cause bursting. Never throw
canister into fire or incinerator. Keep out of reach of children unless otherwise prescribed.
Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP].
Note: The indented statement below is required by the Federal government's Clean Air
Act for all products containing or manufactured with chlorofluorocarbons (CFCs):
WARNING: Contains CFC-12, a substance which harms public health and the
environment by destroying ozone in the upper atmosphere.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A notice similar to the above WARNING has been placed in the “Information For The
Patient” portion of this package insert under the Environmental Protection Agency's
(EPA's) regulations. The patient's warning states that the patient should consult his or her
physician if there are questions about alternatives.
Azmacort
Azmacort
Azmacort
Azmacort is a registered trademark
©2007 Kos Pharmaceuticals, Inc.
Manufactured for: Kos Pharmaceuticals, Inc.
Cranbury, NJ 08512
Printed in USA
INFORMATION FOR THE PATIENT
INFORMATION FOR THE PATIENT
INFORMATION FOR THE PATIENT
INFORMATION FOR THE PATIENT
Your Guide to the
Azmacort
Azmacort
Azmacort
Azmacort®
(triamcinolone acetonide)
Inhalation Aerosol
Special Delivery System
Rx Only
Only
Only
Only
Your doctor has prescribed Azmacort
Azmacort
Azmacort
Azmacort ® (triamcinolone acetonide) Inhalation Aerosol to
help control your asthma. Your Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol is one of the most efficient
and easy-to-use devices available to help you take your prescribed medication. Used
properly, it will effectively and reliably relieve your asthma symptoms.
To receive the maximum benefit, it is very important that you carefully read and follow all
it is very important that you carefully read and follow all
it is very important that you carefully read and follow all
it is very important that you carefully read and follow all
the instructions contained in this booklet
the instructions contained in this booklet
the instructions contained in this booklet
the instructions contained in this booklet for the daily use and care of your Azm
Azm
Azm
Azmacort
acort
acort
acort
Inhalation Aerosol.
IMPORTANT NOTE:
IMPORTANT NOTE:
IMPORTANT NOTE:
IMPORTANT NOTE: If you've used other metered-dose inhalers before, you may expect
the Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol to deliver a noticeable “blast” of medication into your
mouth.
Your AZMACORT Inhalation Aerosol, however, is desig
Your AZMACORT Inhalation Aerosol, however, is desig
Your AZMACORT Inhalation Aerosol, however, is desig
Your AZMACORT Inhalation Aerosol, however, is designed to provide a gentle mist, not a
ned to provide a gentle mist, not a
ned to provide a gentle mist, not a
ned to provide a gentle mist, not a
““““blast,
blast,
blast,
blast,”””” when used.
when used.
when used.
when used.
This gentle action makes it possible for your medication to be more effectively delivered
into the passageways to your lungs, with very little left to linger in your mouth. In fact, you
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
may not even feel the medication entering your mouth, but rest assured, that is how the
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol works.
IMPORTANT:
IMPORTANT:
IMPORTANT:
IMPORTANT: Please read all instructions in this guide carefully before using your
Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol.
BEFORE STARTING TO TAKE THIS MEDI
BEFORE STARTING TO TAKE THIS MEDI
BEFORE STARTING TO TAKE THIS MEDI
BEFORE STARTING TO TAKE THIS MEDICINE, TELL YOUR DOCTOR:
CINE, TELL YOUR DOCTOR:
CINE, TELL YOUR DOCTOR:
CINE, TELL YOUR DOCTOR:
• If you are pregnant or intending to become pregnant.
• If you are breast-feeding a baby.
• If you are allergic to Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol or any other orally inhaled
glucocorticoid.
• If you are taking other medications. In some circumstances, this medication may not
be suitable and your doctor may wish to give you a different medicine.
PREPARE YOUR AZMACORT
PREPARE YOUR AZMACORT
PREPARE YOUR AZMACORT
PREPARE YOUR AZMACORT INHALATION AEROSOL
INHALATION AEROSOL
INHALATION AEROSOL
INHALATION AEROSOL
INHALER FOR USE
INHALER FOR USE
INHALER FOR USE
INHALER FOR USE
STEP 1
STEP 1
STEP 1
STEP 1
1.
1.
1.
1. Line up the arrows on the inhaler.
STEP 2
STEP 2
STEP 2
STEP 2
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2.
2.
2.
2. Gently pull the inhaler to its fully extended position. You will see the valve (small hole)
where the medication will come out.
STEP 3
STEP 3
STEP 3
STEP 3
3.
3.
3.
3. Adjust the inhaler into an “L” shape. It is hinged to swing in one direction only.
STEP 4
STEP 4
STEP 4
STEP 4
4.
4.
4.
4. The ridge on the top part of the inhaler should fit into the notch on the bottom part.
STEP 5
STEP 5
STEP 5
STEP 5
5. Remove the mouthpiece cap.
5. Remove the mouthpiece cap.
5. Remove the mouthpiece cap.
5. Remove the mouthpiece cap. To prepare your Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol for use, the
inhaler must be primed prior to the first use. To prime, hold the inhaler upright, with the
mouthpiece facing away from you. Shake the inhaler gently, then press the canister firmly
and quickly. Repeat this procedure again so a total of 2 puffs are released. Your Azmacort
Azmacort
Azmacort
Azmacort
Inhalation Aerosol is now ready for use.
Repriming is only necessary when your inhaler has not been used for more than 3 days.
To reprime, shake the inhaler and release one puff. Repeat this procedure again so a total
of two puffs are released.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
USING YOUR AZMACORT INHALATION AEROSOL INHALER
USING YOUR AZMACORT INHALATION AEROSOL INHALER
USING YOUR AZMACORT INHALATION AEROSOL INHALER
USING YOUR AZMACORT INHALATION AEROSOL INHALER
STEP 6
STEP 6
STEP 6
STEP 6
6.
6.
6.
6. The metal Azmacort
Azmacort
Azmacort
Azmacort canister has already been inserted into the inhaler. Once you have
opened the inhaler, shake it well before each use. IMPORTANT: You must shake the
IMPORTANT: You must shake the
IMPORTANT: You must shake the
IMPORTANT: You must shake the
inhaler each and every time before inhali
inhaler each and every time before inhali
inhaler each and every time before inhali
inhaler each and every time before inhaling the medication.
ng the medication.
ng the medication.
ng the medication. If your doctor has instructed
you to take more than one breath of medication at a time, you must shake the inhaler
you must shake the inhaler
you must shake the inhaler
you must shake the inhaler
EACH TIME before each inhalation of medication, NOT JUST ONCE.
EACH TIME before each inhalation of medication, NOT JUST ONCE.
EACH TIME before each inhalation of medication, NOT JUST ONCE.
EACH TIME before each inhalation of medication, NOT JUST ONCE.
STEP 7
STEP 7
STEP 7
STEP 7
7. Breathe out to empty your lungs completely before using the inhaler!
7. Breathe out to empty your lungs completely before using the inhaler!
7. Breathe out to empty your lungs completely before using the inhaler!
7. Breathe out to empty your lungs completely before using the inhaler! This is important
to make sure that you can breathe the medication deeply into your lungs.
STEP 8
STEP 8
STEP 8
STEP 8
8.
8.
8.
8. Place mouthpiece into your mouth, and close your lips tightly around it. Press down
firmly and steadily on the metal canister while breathing in slowly and deeply THROUGH
THROUGH
THROUGH
THROUGH
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YOUR MOUTH ONLY
YOUR MOUTH ONLY
YOUR MOUTH ONLY
YOUR MOUTH ONLY. (If necessary, pinch your nose closed.) Be sure to release your
finger pressure from the top of the canister after the medication is released.
Remember, the Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol delivers a gentle mi
gentle mi
gentle mi
gentle mistststst of medication, so don't
be surprised if you hardly feel it.
Do not remove the inhaler from your mouth after breathing in the medication. Hold your
Do not remove the inhaler from your mouth after breathing in the medication. Hold your
Do not remove the inhaler from your mouth after breathing in the medication. Hold your
Do not remove the inhaler from your mouth after breathing in the medication. Hold your
breath for 10 seconds with the inhaler STILL in your mouth, THEN remove the inhaler and
breath for 10 seconds with the inhaler STILL in your mouth, THEN remove the inhaler and
breath for 10 seconds with the inhaler STILL in your mouth, THEN remove the inhaler and
breath for 10 seconds with the inhaler STILL in your mouth, THEN remove the inhaler and
breathe out very
breathe out very
breathe out very
breathe out very slowly.
slowly.
slowly.
slowly.
Unlike the other inhalers you may have used, you will not feel the medication impact the
back of your mouth. This is because of the unique design of the Azmacort
Azmacort
Azmacort
Azmacort Inhalation
Aerosol delivery system.
STEP 9
STEP 9
STEP 9
STEP 9
9.
9.
9.
9. If your doctor has told you to take more than one breath of medication at a time: WAIT
WAIT
WAIT
WAIT
AT LEAST 60 SECONDS
AT LEAST 60 SECONDS
AT LEAST 60 SECONDS
AT LEAST 60 SECONDS between each one, then start again at Step 6.
STEP 10
STEP 10
STEP 10
STEP 10
10.
10.
10.
10. After the prescribed number of inhalations, thoroughly rinse out your mouth with water.
NOTE:
NOTE:
NOTE:
NOTE: If your mouth becomes sore or develops a rash, be sure to mention this to your
physician, but do not stop using your inhaler unless instructed to do so.
DOSAGE: USE ONLY AS DIRECTED BY YOUR PHYSICIAN
DOSAGE: USE ONLY AS DIRECTED BY YOUR PHYSICIAN
DOSAGE: USE ONLY AS DIRECTED BY YOUR PHYSICIAN
DOSAGE: USE ONLY AS DIRECTED BY YOUR PHYSICIAN
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WARNING: Azmacort
WARNING: Azmacort
WARNING: Azmacort
WARNING: Azmacort® (triamcinolone acetonide) Inhalation Aerosol contains medication
that is intended for treatment of your asthma. It does not contain medication intended to
provide rapid relief of your breathing difficulties during an asthma attack.
It is very important that you use Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol regularly at the intervals
recommended by your doctor, and not as an emergency measure. Your physician will
decide whether other medication is needed, should you require immediate relief.
CAUTION: CONTENTS OF CANISTER UNDER PRESSURE.
CAUTION: CONTENTS OF CANISTER UNDER PRESSURE.
CAUTION: CONTENTS OF CANISTER UNDER PRESSURE.
CAUTION: CONTENTS OF CANISTER UNDER PRESSURE.
Do not puncture. Do not store near heat or open flame. Exposure to temperatures above
120°F may cause bursting. Never throw canisters into a fire or incinerator. Please keep
out of the reach of children.
Note: The indented statement below is required by the Federal government's Clean Air
Act for all products containing or manufactured with chlorofluorocarbons (CFCs):
This product contains CFC-12, a substance which harms the environment by destroying
ozone in the upper atmosphere.
Your physician has determined that this product is likely to help your personal health. USE
USE
USE
USE
THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY
THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY
THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY
THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY
YOUR PHYSICIAN.
YOUR PHYSICIAN.
YOUR PHYSICIAN.
YOUR PHYSICIAN. If you have any questions about alternatives, consult with your
physician.
IMPORTANT TIPS FOR USING YOUR AZMACORT INHALATION AEROSOL INHALER
IMPORTANT TIPS FOR USING YOUR AZMACORT INHALATION AEROSOL INHALER
IMPORTANT TIPS FOR USING YOUR AZMACORT INHALATION AEROSOL INHALER
IMPORTANT TIPS FOR USING YOUR AZMACORT INHALATION AEROSOL INHALER
• Always use only as directed by your physician. Do not use it more often than
instructed; do not skip doses.
• Follow all instructions in this booklet very closely and carefully for best results,
especially those for use and cleaning.
• Remember, repriming is only necessary when the inhaler has not been used for more
than 3 days. To reprime, shake the inhaler gently and release one puff. Repeat this
procedure again so that a total of two puffs have been released. Do not reprime
between more frequent usage.
• Please Note:
Please Note:
Please Note:
Please Note:
You will receive a new Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol unit each time you refill your
prescription. This is done to assure optimal working order of the unique Azmacort
Azmacort
Azmacort
Azmacort
Inhalation Aerosol spacer device/delivery system. In addition, a new Azmacort
Azmacort
Azmacort
Azmacort
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Inhalation Aerosol will guard against a build-up of the drug on the barrel portion of
the device, maximizing the cleanliness of your unit. The cost of Azmacort
Azmacort
Azmacort
Azmacort Inhalation
Aerosol is MINIMALLY affected by including a new inhaler with each prescription.
STORING YOUR AZMACORT INHALATI
STORING YOUR AZMACORT INHALATI
STORING YOUR AZMACORT INHALATI
STORING YOUR AZMACORT INHALATION AEROSOL INHALER
ON AEROSOL INHALER
ON AEROSOL INHALER
ON AEROSOL INHALER
• Keep your inhaler out of the reach of children,
out of the reach of children,
out of the reach of children,
out of the reach of children, unless otherwise prescribed.
• Store your Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol, including the metal canister, at room
temperature.
• Protect from freezing temperatures and direct sunlight.
• For best results, the canister should be at room temperature before use.
• DO NOT
DO NOT
DO NOT
DO NOT use after the date shown as “EXP” on the label or box.
• Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol canisters are for use with Azmacort
Azmacort
Azmacort
Azmacort Inhalation Aerosol
actuators and spacer-mouthpieces only. The actuator and spacer-mouthpiece
should not be used with other aerosol medications.
• REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT
REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT
REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT
REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT
give this medicine to anyone else.
give this medicine to anyone else.
give this medicine to anyone else.
give this medicine to anyone else.
DAILY CARE OF YOUR AZMACORT INHALATION AEROSOL INHALER
DAILY CARE OF YOUR AZMACORT INHALATION AEROSOL INHALER
DAILY CARE OF YOUR AZMACORT INHALATION AEROSOL INHALER
DAILY CARE OF YOUR AZMACORT INHALATION AEROSOL INHALER
Your Azmac
Azmac
Azmac
Azmacort
ort
ort
ort Inhalation Aerosol MUST
MUST
MUST
MUST be cleaned in lukewarm water only once each
day to avoid build-up of medication particles in the inhaler that can block the puff of
medication and interfere with proper operation. The use of soap, detergents, or
disinfectants is unnecessary.
1. IMPORTANT: Remove metal canister from inhaler.
IMPORTANT: Remove metal canister from inhaler.
IMPORTANT: Remove metal canister from inhaler.
IMPORTANT: Remove metal canister from inhaler. Pull canister straight out from
inhaler and place aside. Canister must be removed for proper cleaning of inhaler.
Canister must be removed for proper cleaning of inhaler.
Canister must be removed for proper cleaning of inhaler.
Canister must be removed for proper cleaning of inhaler.
2. Pull apart remaining two plastic parts of inhaler, remove mouthpiece cap, and
gently wash in lukewarm water.
Dry thoroughly.
Dry thoroughly.
Dry thoroughly.
Dry thoroughly.
3. Snap the two plastic parts of the inhaler back together; push closed. Replace
mouthpiece cap. Reinsert metal canister by gently turning while inserting. The
canister should fit snugly without falling out.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW TO CHECK CONTENTS OF YOUR CANISTER
HOW TO CHECK CONTENTS OF YOUR CANISTER
HOW TO CHECK CONTENTS OF YOUR CANISTER
HOW TO CHECK CONTENTS OF YOUR CANISTER
Shaking the canister will NOT
NOT
NOT
NOT give you a good estimate of how much Azmacort
Azmacort
Azmacort
Azmacort®
(triamcinolone acetonide) Inhalation Aerosol is left.
We have included a convenient check-off chart to assist you in keeping track of
medication puffs used. This will help assure that you receive the 240 “Full Puffs” of
medication present.
FURTHER INFORMATION
FURTHER INFORMATION
FURTHER INFORMATION
FURTHER INFORMATION
• This leaflet does not contain the complete information about your medication.
• If you have any further questions, or are not sure about something, you should ask
your doctor or pharmacist.
• You may want to read this leaflet again. Please DO NOT THROW IT AWAY
DO NOT THROW IT AWAY
DO NOT THROW IT AWAY
DO NOT THROW IT AWAY until you
have finished this canister.
Azmacort is a registered trademark
©2007 Kos Pharmaceuticals, Inc.
Manufactured for: Kos Pharmaceuticals, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cranbury, NJ 08512
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:37.303193
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018117s042lbl.pdf', 'application_number': 18117, 'submission_type': 'SUPPL ', 'submission_number': 42}
|
11,165
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Page 1
Rev. May 2003
Rx only
Azmacort®
(triamcinolone acetonide)
Inhalation Aerosol
For Oral Inhalation Only
Shake Well Before Using
DESCRIPTION
Triamcinolone acetonide, USP, the active ingredient in Azmacort® Inhalation Aerosol, is a
corticosteroid with a molecular weight of 434.5 and with the chemical designation 9-Fluoro-
11ß,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone.
(C24H31FO6).
Azmacort Inhalation Aerosol is a metered-dose aerosol unit containing a microcrystalline
suspension of triamcinolone acetonide in the propellant dichlorodifluoromethane and dehydrated
alcohol USP 1% w/w. Each canister contains 60 mg triamcinolone acetonide. The canister must
be primed prior to the first use. After an initial priming of 2 actuations, each actuation delivers
200 mcg triamcinolone acetonide from the valve and 100 mcg from the spacer-mouthpiece under
defined in vitro test conditions. The canister will remain primed for 3 days. If the canister is not
used for more than 3 days, then it should be reprimed with 2 actuations. There are at least 240
actuations in one Azmacort Inhalation Aerosol canister. After 240 actuations, the amount
delivered per actuation may not be consistent and the unit should be discarded.
CLINICAL PHARMACOLOGY
Triamcinolone acetonide is a more potent derivative of triamcinolone. Although triamcinolone
itself is approximately one to two times as potent as prednisone in animal models of
inflammation, triamcinolone acetonide is approximately 8 times more potent than prednisone.
The precise mechanism of the action of glucocorticoids in asthma is unknown. However, the
inhaled route makes it possible to provide effective local anti-inflammatory activity with reduced
systemic corticosteroid effects. Though highly effective for asthma, glucocorticoids do not affect
asthma symptoms immediately. While improvement in asthma may occur as soon as one week
after initiation of Azmacort Inhalation Aerosol therapy, maximum improvement may not be
achieved for 2 weeks or longer.
Based upon intravenous dosing of triamcinolone acetonide phosphate ester, the half-life of
triamcinolone acetonide was reported to be 88 minutes. The volume of distribution (Vd) reported
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2
was 99.5 L (SD ± 27.5) and clearance was 45.2 L/hour (SD ± 9.1) for triamcinolone acetonide.
The plasma half-life of glucocorticoids does not correlate well with the biologic half-life.
The pharmacokinetics of radiolabeled triamcinolone acetonide [14C] were evaluated following a
single oral dose of 800 mcg to healthy male volunteers. Radiolabeled triamcinolone acetonide
was found to undergo relatively rapid absorption following oral administration with maximum
plasma triamcinolone acetonide and [14C]-derived radioactivity occurring between 1.5 and 2
hours. Plasma protein binding of triamcinolone acetonide appears to be relatively low and
consistent over a wide plasma triamcinolone acetonide concentration range as a function of time.
The overall mean percent fraction bound was approximately 68%.
The metabolism and excretion of triamcinolone acetonide were both rapid and extensive with no
parent compound being detected in the plasma after 24 hours post-dose and a low ratio (10.6%)
of parent compound AUC0-∞ to total [14C] radioactivity AUC0-∞. Greater than 90% of the oral
[14C]-radioactive dose was recovered within 5 days after administration in 5 out of the 6 subjects
in the study. Of the recovered [14C]-radioactivity, approximately 40% and 60% were found in the
urine and feces, respectively.
Three metabolites of triamcinolone acetonide have been identified. They are 6ß-
hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6ß-
hydroxytriamcinolone acetonide. All three metabolites are expected to be substantially less
active than the parent compound due to (a) the dependence of anti-inflammatory activity on the
presence of a 21-hydroxyl group, (b) the decreased activity observed upon 6-hydroxylation, and
(c) the markedly increased water solubility favoring rapid elimination. There appeared to be
some quantitative differences in the metabolites among species. No differences were detected in
metabolic pattern as a function of route of administration.
CLINICAL TRIALS
Double-blind, placebo-controlled efficacy and safety studies have been conducted in asthma
patients with a range of asthma severities, from those patients with mild disease to those with
severe disease requiring oral steroid therapy.
The efficacy and safety of Azmacort Inhalation Aerosol given twice daily was demonstrated in
two placebo-controlled clinical trials. In two separate studies, 222 asthmatic patients were
randomized to receive either Azmacort Inhalation Aerosol 400 mcg twice daily or matching
placebo for a treatment period of 6 weeks. Patients were adult asthmatics who were using inhaled
beta2-agonists on more than an occasional basis (at least three times weekly), either without or
with inhaled corticosteroids, for control of their asthma symptoms. For the combined studies,
48% (52/109) patients randomized to placebo and 41% (46/113) patients randomized to
Azmacort Inhalation Aerosol treatment were previously treated with inhaled corticosteroids.
Results of weekly lung function tests (FEV1) from one of these trials is presented graphically
below. Results of the second study are presented in tabular form as the changes in asthma
measures from baseline to the end of the treatment period.
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Page 3
Mean Changes in Asthma Measures from Baseline to Endpointa
All-Treated Patients
Results from a Placebo-Controlled, 6 Week Study
Asthma Measure
Placebo
(N=61)
Azmacort 400 mcg bid
(N=60)
Percent Change in FEV1(%)
2.8%
17.5%
Increase in Morning Peak
Flow Rate (L/min)
6.7
45.9
Decrease in Albuterol Use
(puffs/day)
0.6
3.4
Decrease in Daily Asthma Symptom
Score (units/day)b
0.5
2.3
aEndpoint Results are obtained from the last evaluable data, regardless of whether the patient completed 6 weeks of
treatment
bScale (0-6) with 0 = no symptom: Maximum Score (AM + PM) =12
In both studies, treatment with Azmacort Inhalation Aerosol (400 mcg twice daily) resulted in
significant improvements in all clinical asthma measures (lung functions, asthma symptoms, use
of as-needed beta2-agonist medications) when compared to placebo.
INDICATIONS
Azmacort Inhalation Aerosol is indicated in the maintenance treatment of asthma as
prophylactic therapy. Azmacort Inhalation Aerosol is also indicated for asthma patients who
require systemic corticosteroid administration, where adding Azmacort may reduce or eliminate
the need for the systemic corticosteroids.
Azmacort Inhalation Aerosol is NOT indicated for the relief of acute bronchospasm.
CONTRAINDICATIONS
Azmacort Inhalation Aerosol is contraindicated in the primary treatment of status asthmaticus or
other acute episodes of asthma where intensive measures are required.
Hypersensitivity to triamcinolone acetonide or any of the other ingredients in this preparation
contraindicates its use.
WARNINGS
Particular care is needed in patients who are transferred from systemically active corticosteroids
to Azmacort Inhalation Aerosol because deaths due to adrenal insufficiency have occurred in
asthmatic patients during and after transfer from systemic corticosteroids to aerosolized steroids
in recommended doses. After withdrawal from systemic corticosteroids, a number of months is
usually required for recovery of hypothalamic-pituitary-adrenal (HPA) function. For some
patients who have received large doses of oral steroids for long periods of time before therapy
with Azmacort Inhalation Aerosol is initiated, recovery may be delayed for one year or longer.
During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal
insufficiency when exposed to trauma, surgery, or infections, particularly gastroenteritis or other
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Page 4
conditions with acute electrolyte loss. Although Azmacort Inhalation Aerosol may provide
control of asthmatic symptoms during these episodes, in recommended doses it supplies only
normal physiological amounts of corticosteroid systemically and does NOT provide the
increased systemic steroid which is necessary for coping with these emergencies.
During periods of stress or a severe asthmatic attack, patients who have been recently withdrawn
from systemic corticosteroids should be instructed to resume systemic steroids (in large doses)
immediately and to contact their physician for further instruction. These patients should also be
instructed to carry a warning card indicating that they may need supplementary systemic steroids
during periods of stress or a severe asthma attack.
Localized infections with Candida albicans have occurred infrequently in the mouth and
pharynx. These areas should be examined by the treating physician at each patient visit. The
percentage of positive mouth and throat cultures for Candida albicans did not change during a
year of continuous therapy. The incidence of clinically apparent infection is low (2.5%). These
infections may disappear spontaneously or may require treatment with appropriate antifungal
therapy or discontinuance of treatment with Azmacort Inhalation Aerosol.
Children who are on immunosuppressant drugs are more susceptible to infections than healthy
children. Chickenpox and measles, for example, can have a more serious or even fatal course in
children on immunosuppressant doses of corticosteroids. In such children, or in adults who have
not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy
with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as
appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be
considered.
Azmacort Inhalation Aerosol is not to be regarded as a bronchodilator and is not indicated for
rapid relief of bronchospasm.
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase
in wheezing following dosing. If bronchospasm occurs following use of Azmacort Inhalation
Aerosol, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment
with Azmacort Inhalation Aerosol should be discontinued and alternative treatment should be
instituted.
Patients should be instructed to contact their physician immediately when episodes of asthma
which are not responsive to bronchodilators occur during the course of treatment with Azmacort
Inhalation Aerosol. During such episodes, patients may require therapy with systemic
corticosteroids.
The use of Azmacort Inhalation Aerosol with systemic prednisone, dosed either daily or on
alternate days, could increase the likelihood of HPA suppression compared to a therapeutic dose
of either one alone. Therefore, Azmacort Inhalation Aerosol should be used with caution in
patients already receiving prednisone treatment for any disease.
Transfer of patients from systemic steroid therapy to Azmacort Inhalation Aerosol may unmask
allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis,
conjunctivitis, and eczema.
PRECAUTIONS
During withdrawal from oral steroids, some patients may experience symptoms of systemically
active steroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite
maintenance or even improvement of respiratory function. (See DOSAGE AND
ADMINISTRATION.) Although steroid withdrawal effects are usually transient and not severe,
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Page 5
severe and even fatal exacerbation of asthma can occur if the previous daily oral corticosteroid
requirement had significantly exceeded 10 mg/day of prednisone or equivalent.
In responsive patients, inhaled corticosteroids will often permit control of asthmatic symptoms
with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.
Since triamcinolone acetonide is absorbed into the circulation and can be systemically active, the
beneficial effects of Azmacort Inhalation Aerosol in minimizing or preventing HPA dysfunction
may be expected only when recommended dosages are not exceeded.
Suppression of HPA function has been reported in volunteers who received 4000 mcg daily of
triamcinolone acetonide by oral inhalation. In addition, suppression of HPA function has been
reported in some patients who have received recommended doses for as little as 6 to 12 weeks.
Since the response of HPA function to inhaled corticosteroids is highly individualized, the
physician should consider this information when treating patients.
When used at excessive doses or at recommended doses in a small number of susceptible
individuals, systemic corticosteroid effects such as hypercorticoidism and adrenal suppression
may appear. If such changes occur, Azmacort® (triamcinolone acetonide) Inhalation Aerosol
should be discontinued slowly, consistent with accepted procedures for reducing systemic steroid
therapy and for management of asthma symptoms.
Azmacort Inhalation Aerosol should be used with caution, if at all, in patients with active or
quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial,
parasitic, or viral infections; or ocular herpes simplex.
The long-term local and systemic effects of Azmacort Inhalation Aerosol in human subjects are
still not fully known. While there has been no clinical evidence of adverse experiences, the
effects resulting from chronic use of Azmacort Inhalation Aerosol on developmental or
immunologic processes in the mouth, pharynx, trachea, and lung are unknown.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with
these drugs should be observed carefully for any evidence of systemic corticosteroid effects
including suppression of growth in children. Particular care should be taken in observing patients
postoperatively or during periods of stress for evidence of a decrease in adrenal function.
Information for Patients: Patients being treated with Azmacort Inhalation Aerosol should
receive the following information and instructions. This information is intended to aid them in
the safe and effective use of this medication. It is not a complete disclosure of all possible
adverse or intended effects.
Patients should use Azmacort Inhalation Aerosol at regular intervals as directed. Results of
clinical trials indicate that significant improvement in asthma may occur by 1 week, but
maximum benefit may not be achieved for 2 weeks or more. The patient should not increase the
prescribed dosage but should contact the physician if symptoms do not improve or if the
condition worsens.
In clinical studies and post-marketing experience with Azmacort Inhalation Aerosol, local
infections of the oropharynx with Candida albicans have occurred. When such an infection
develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy
while remaining on treatment with Azmacort Inhalation Aerosol. However, at times therapy
with Azmacort Inhalation Aerosol may need to be interrupted.
Patients should be instructed to track their use of Azmacort Inhalation Aerosol and to dispose of
the canister after 240 actuations since reliable dose delivery cannot be assured after 240 doses.
Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid
exposure to chickenpox or measles and, if exposed, to obtain medical advice.
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Page 6
Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of treatment-related
carcinogenicity was demonstrated after two years of once daily gavage of triamcinolone
acetonide at doses of 0.05, 0.2, and 1.0 mcg/kg (approximately 0.02, 0.07, and 0.4% of the
maximum recommended human daily inhalation dose on a mcg/m2 basis) in the rat and 0.1, 0.6,
and 3.0 mcg/kg (approximately 0.02, 0.1, and 0.6% of the maximum recommended human daily
inhalation dose on a mcg/m2 basis) in a mouse.
Mutagenesis studies with triamcinolone acetonide have not been carried out.
No evidence of impaired fertility was manifested when oral doses of up to 15.0 mcg/kg (8% of
the maximum recommended human daily inhalation dose on a mcg/m2 basis) were administered
to female and male rats. However, triamcinolone acetonide at oral doses of 8 mcg/kg
(approximately 4% of the maximum recommended human daily inhalation dose on a mcg/m2
basis) caused dystocia and prolonged delivery and at oral doses of 5.0 mcg/kg (approximately
2.5% of the maximum recommended human daily inhalation dose on a mcg/m2 basis) and above
caused increases in fetal resorptions and stillbirths and decreases in pup body weight and
survival. At a lower dose of 1.0 mcg/kg (approximately 0.5% of the maximum recommended
human daily inhalation dose on a mcg/m2 basis) it did not induce the above mentioned effects.
Pregnancy: Pregnancy Category C. Triamcinolone acetonide has been shown to be teratogenic
at inhalational doses of 20, 40, and 80 mcg/kg in rats (approximately 0.1, 0.2, and 0.4 times the
maximum recommended human daily inhalation dose on a mcg/m2 basis, respectively), in rabbits
at the same doses (approximately 0.2, 0.4, and 0.8 times the maximum recommended human
daily inhalation dose on a mcg/m2 basis, respectively) and in monkeys, at an inhalational dose of
500 mcg/kg (approximately 5 times the maximum recommended human daily inhalation dose on
a mcg/m2 basis). Dose related teratogenic effects in rats and rabbits included cleft palate and/or
internal hydrocephaly and axial skeletal defects whereas the teratogenic effects observed in the
monkey were CNS and/or cranial malformations. There are no adequate and well controlled
studies in pregnant women. Triamcinolone acetonide should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Experience with oral glucocorticoids since their introduction in pharmacologic as opposed to
physiologic doses suggests that rodents are more prone to teratogenic effects from
glucocorticoids than humans. In addition, because there is a natural increase in glucocorticoid
production during pregnancy, most women will require a lower exogenous steroid dose and
many will not need glucocorticoid treatment during pregnancy.
Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving
corticosteroids during pregnancy. Such infants should be carefully observed.
Nursing Mothers: It is not known whether triamcinolone acetonide is excreted in human milk.
Because other corticosteroids are excreted in human milk, caution should be exercised when
Azmacort Inhalation Aerosol is administered to nursing women.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients below the
age of 6. Oral corticosteroids have been shown to cause growth suppression in children and
teenagers, particularly with higher doses over extended periods. If a child or teenager on any
corticosteroid appears to have growth suppression, the possibility that they are particularly
sensitive to this effect of steroids should be considered.
Geriatric Use: Clinical studies of Azmacort Inhalation Aerosol did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should
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Page 7
be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.
ADVERSE REACTIONS
The table below describes the incidence of common adverse experiences based upon three
placebo-controlled, multicenter US clinical trials of 507 patients (297 female and 210 male
adults (age range 18-64)). These trials included asthma patients who had previously received
inhaled beta2-agonists alone, as well as those who previously required inhaled corticosteroid
therapy for the control of their asthma. The patients were treated with Azmacort Inhalation
Aerosol (including doses ranging from 200 to 800 mcg twice daily for 6 weeks) or placebo.
Adverse Events Occurring at an Incidence of Greater Than 3%
and Greater Than Placebo
Adverse Event
Azmacort Dose
Placebo
200 mcg bid
(n=57)
400 mcg bid
(n=170)
800 mcg bid
(n=57)
(n=167)
Sinusitis
5 (9%)
7 (4%)
1 (2%)
6 (4%)
Pharyngitis
4 (7%)
42 (25%)
10 (18%)
19 (11%)
Headache
4 (7%)
35 (21%)
7 (12%)
24 (14%)
Flu Syndrome
2 (4%)
8 (5%)
1 (2%)
5 (3%)
Back Pain
2 (4%)
3 (2%)
2 (4%)
3 (2%)
Adverse events that occurred at an incidence of 1-3% in the overall Azmacort Inhalation
Aerosol treatment group and greater than placebo included:
Body as a whole:
facial edema, pain, abdominal pain, photosensitivity
Digestive system:
diarrhea, oral monilia, toothache, vomiting
Metabolic and Nutrition:
weight gain
Musculoskeletal system:
bursitis, myalgia, tenosynovitis
Nervous system:
dry mouth
Organs of special sense:
rash
Respiratory system:
chest congestion, voice alteration
Urogenital system:
cystitis, urinary tract infection, vaginal monilia
In older controlled clinical trials of steroid dependent asthmatics, urticaria was reported rarely.
Anaphylaxis was not reported in these controlled trials. Typical steroid withdrawal effects
including muscle aches, joint aches, and fatigue were noted in clinical trials when patients were
transferred from oral steroid therapy to Azmacort Inhalation Aerosol. Easy bruisability was also
noted in these trials.
Hoarseness, dry throat, irritated throat, dry mouth, facial edema, increased wheezing, and cough
have been reported. These adverse effects have generally been mild and transient. Cases of oral
candidiasis occurring with clinical use have been reported. (See WARNINGS.)
Post Marketing: In addition to adverse events reported from clinical trials, the following events
have been identified during post approval use of Azmacort Inhalation Aerosol where these
events were reported voluntarily from a population of unknown size, and the frequency of
occurrence cannot be determined precisely. These include rare reports of anaphylaxis, cataracts,
and glaucoma.
OVERDOSAGE
There are no data available on the effects of acute or chronic overdose. However, acute
overdosing with Azmacort Inhalation Aerosol is unlikely in view of the total amount of active
ingredient present and the route of administration. The maximum total daily dose (1600 mcg) has
been well tolerated when administered as a single dose of 16 consecutive inhalations to adult
This label may not be the latest approved by FDA.
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Page 8
asthmatics in a controlled clinical trial. Chronic overdosage may result in signs/symptoms of
hypercorticoidism. (See PRECAUTIONS.) The risk of candidiasis could also be increased.
DOSAGE AND ADMINISTRATION
Adults: The usual recommended dosage is two inhalations (200 mcg) given three to four times a
day or four inhalations (400 mcg) given twice daily. The maximal daily intake should not exceed
16 inhalations (1600 mcg) in adults. Higher initial doses (12 to 16 inhalations per day) may be
considered in patients with more severe asthma.
Children 6 to 12 Years of Age: The usual recommended dosage is one or two inhalations (100
to 200 mcg) given three to four times a day or two to four inhalations (200 to 400 mcg) given
twice daily. The maximal daily intake should not exceed 12 inhalations (1200 mcg) in children 6
to 12 years of age. Insufficient clinical data exist with respect to the safety and efficacy of the
administration of Azmacort Inhalation Aerosol to children below the age of 6. The long-term
effects of inhaled steroids, including Azmacort Inhalation Aerosol, on growth are still not fully
known.
Rinsing the mouth after inhalation is advised.
Different considerations must be given to the following groups of patients in order to obtain the
full therapeutic benefit of Azmacort Inhalation Aerosol:
Note: In all patients, it is desirable to titrate to the lowest effective dose once asthma
stability has been achieved.
Patients Not Receiving Systemic Corticosteroids: Patients who require maintenance therapy of
their asthma may benefit from treatment with Azmacort Inhalation Aerosol at the doses
recommended above. In patients who respond to Azmacort Inhalation Aerosol, improvement in
pulmonary function is usually apparent within one to two weeks after the initiation of therapy.
Patients Maintained on Systemic Corticosteroids: Clinical studies have shown that Azmacort
Inhalation Aerosol may be effective in the management of asthmatics dependent or maintained
on systemic corticosteroids and may permit replacement or significant reduction in the dosage of
systemic corticosteroids.
The patient’s asthma should be reasonably stable before treatment with Azmacort Inhalation
Aerosol is started. Initially, Azmacort Inhalation Aerosol should be used concurrently with the
patient’s usual maintenance dose of systemic corticosteroid. After approximately one week,
gradual withdrawal of the systemic corticosteroid is started by reducing the daily or alternate
daily dose. Reductions may be made after an interval of one or two weeks, depending on the
response of the patient. A slow rate of withdrawal is strongly recommended. Generally, these
decrements should not exceed 2.5 mg of prednisone or its equivalent. During withdrawal, some
patients may experience symptoms of systemic corticosteroid withdrawal, e.g., joint and/or
muscular pain, lassitude, and depression, despite maintenance or even improvement in
pulmonary function. Such patients should be encouraged to continue with the inhaler but should
be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency
occurs, the systemic corticosteroid doses should be increased temporarily and thereafter
withdrawal should continue more slowly. Inhaled corticosteroids should be used with caution
when used chronically in patients receiving prednisone regimens, either daily or alternate day.
(See WARNINGS.)
During periods of stress or a severe asthma attack, transfer patients may require supplementary
treatment with systemic corticosteroids.
Directions for Use: An illustrated leaflet of patient instructions for proper use accompanies each
package of Azmacort Inhalation Aerosol.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 9
HOW SUPPLIED
Azmacort Inhalation Aerosol contains 60 mg triamcinolone acetonide in a 20 gram package
which delivers at least 240 actuations. It is supplied with a white plastic actuator, a white plastic
spacer-mouthpiece and patient’s leaflet of instructions: box of one. NDC 0075-0060-37. Each
actuation delivers 200 mcg triamcinolone acetonide from the valve and 100 mcg from the spacer-
mouthpiece under defined in vitro test conditions.
Avoid spraying in eyes.
For best results, the canister should be at room temperature before use.
Shake well before using.
CONTENTS UNDER PRESSURE. Do not puncture. Do not use or store near heat or open
flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire
or incinerator. Keep out of reach of children unless otherwise prescribed. Store at Controlled
Room Temperature 20 to 25°C (68 to 77°F) [see USP].
Note: The indented statement below is required by the Federal government’s Clean Air Act for
all products containing or manufactured with chlorofluorocarbons (CFCs):
WARNING: Contains CFC-12, a substance which harms public health and the environment
by destroying ozone in the upper atmosphere.
A notice similar to the above WARNING has been placed in the “Information For The Patient”
portion of this package insert under the Environmental Protection Agency’s (EPA’s) regulations.
The patient’s warning states that the patient should consult his or her physician if there are
questions about alternatives.
Rx only
Aventis Pharmaceuticals Inc.
Bridgewater, NJ 08807 USA
©2002 Aventis Pharmaceuticals Inc.
Rev. May 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 10
INFORMATION FOR THE PATIENT
Your Guide to the
Special Delivery System
Your doctor has prescribed Azmacort® (triamcinolone acetonide) Inhalation Aerosol to help
control your asthma. Your Azmacort Inhalation Aerosol is one of the most efficient and easy-to-
use devices available to help you take your prescribed medication. Used properly, it will
effectively and reliably relieve your asthma symptoms.
To receive the maximum benefit, it is very important that you carefully read and follow all
the instructions contained in this booklet for the daily use and care of your Azmacort
Inhalation Aerosol.
IMPORTANT NOTE: If you’ve used other metered-dose inhalers before, you may expect the
Azmacort Inhalation Aerosol to deliver a noticeable “blast” of medication into your mouth.
Your AZMACORT Inhalation Aerosol, however, is designed to provide a gentle mist, not a
“blast,” when used.
This gentle action makes it possible for your medication to be more effectively delivered into the
passageways to your lungs, with very little left to linger in your mouth. In fact, you may not even
feel the medication entering your mouth, but rest assured, that is how the Azmacort Inhalation
Aerosol works.
IMPORTANT: Please read all instructions in this guide carefully before using your Azmacort
Inhalation Aerosol.
BEFORE STARTING TO TAKE THIS MEDICINE, TELL YOUR DOCTOR:
•
If you are pregnant or intending to become pregnant.
•
If you are breast-feeding a baby.
•
If you are allergic to Azmacort Inhalation Aerosol or any other orally inhaled glucocorticoid.
•
If you are taking other medications. In some circumstances, this medication may not be
suitable and your doctor may wish to give you a different medicine.
PREPARE YOUR AZMACORT INHALATION AEROSOL
INHALER FOR USE
STEP 1
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Page 11
1. Line up the arrows on the inhaler.
STEP 2
2. Gently pull the inhaler to its fully extended position. You will see the valve (small hole)
where the medication will come out.
STEP 3
3. Adjust the inhaler into an “L” shape. It is hinged to swing in one direction only.
STEP 4
4. The ridge on the top part of the inhaler should fit into the notch on the bottom part.
STEP 5
5. Remove the mouthpiece cap. To prepare your Azmacort Inhalation Aerosol for use, the
inhaler must be primed prior to the first use. To prime, hold the inhaler upright, with the
mouthpiece facing away from you. Shake the inhaler gently, then press the canister firmly
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Page 12
and quickly. Repeat this procedure again so a total of 2 puffs are released. Your Azmacort
Inhalation Aerosol is now ready for use.
Repriming is only necessary when your inhaler has not been used for more than 3 days. To
reprime, shake the inhaler and release one puff. Repeat this procedure again so a total of two
puffs are released.
USING YOUR AZMACORT INHALATION AEROSOL INHALER
STEP 6
6. The metal Azmacort canister has already been inserted into the inhaler. Once you have
opened the inhaler, shake it well before each use. IMPORTANT: You must shake the
inhaler each and every time before inhaling the medication. If your doctor has instructed
you to take more than one breath of medication at a time, you must shake the inhaler
EACH TIME before each inhalation of medication, NOT JUST ONCE.
STEP 7
7. Breathe out to empty your lungs completely before using the inhaler! This is important to
make sure that you can breathe the medication deeply into your lungs.
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STEP 8
8. Place mouthpiece into your mouth, and close your lips tightly around it. Press down firmly
and steadily on the metal canister while breathing in slowly and deeply THROUGH YOUR
MOUTH ONLY. (If necessary, pinch your nose closed.) Be sure to release your finger
pressure from the top of the canister after the medication is released.
Remember, the Azmacort Inhalation Aerosol delivers a gentle mist of medication, so don’t
be surprised if you hardly feel it.
Do not remove the inhaler from your mouth after breathing in the medication. Hold
your breath for 10 seconds with the inhaler STILL in your mouth, THEN remove the
inhaler and breathe out very slowly.
Unlike the other inhalers you may have used, you will not feel the medication impact the
back of your mouth. This is because of the unique design of the Azmacort Inhalation Aerosol
delivery system.
STEP 9
9. If your doctor has told you to take more than one breath of medication at a time: WAIT AT
LEAST 60 SECONDS between each one, then start again at Step 6.
STEP 10
10. After the prescribed number of inhalations, thoroughly rinse out your mouth with water.
NOTE: If your mouth becomes sore or develops a rash, be sure to mention this to your
physician, but do not stop using your inhaler unless instructed to do so.
DOSAGE: USE ONLY AS DIRECTED BY YOUR PHYSICIAN
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 14
WARNING: Azmacort® (triamcinolone acetonide) Inhalation Aerosol contains medication that
is intended for treatment of your asthma. It does not contain medication intended to provide rapid
relief of your breathing difficulties during an asthma attack.
It is very important that you use Azmacort Inhalation Aerosol regularly at the intervals
recommended by your doctor, and not as an emergency measure. Your physician will decide
whether other medication is needed, should you require immediate relief.
CAUTION: CONTENTS OF CANISTER UNDER PRESSURE.
Do not puncture. Do not store near heat or open flame. Exposure to temperatures above 120°F
may cause bursting. Never throw canisters into a fire or incinerator. Please keep out of the reach
of children.
Note: The indented statement below is required by the Federal government’s Clean Air Act for
all products containing or manufactured with chlorofluorocarbons (CFCs):
This product contains CFC-12, a substance which harms the environment by destroying ozone
in the upper atmosphere.
Your physician has determined that this product is likely to help your personal health. USE
THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY
YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.
IMPORTANT TIPS FOR USING YOUR AZMACORT INHALATION AEROSOL
INHALER
•
Always use only as directed by your physician. Do not use it more often than instructed; do
not skip doses.
•
Follow all instructions in this booklet very closely and carefully for best results, especially
those for use and cleaning.
•
Remember, repriming is only necessary when the inhaler has not been used for more than 3
days. To reprime, shake the inhaler gently and release one puff. Repeat this procedure again
so that a total of two puffs have been released. Do not reprime between more frequent usage.
•
Please Note:
You will receive a new Azmacort Inhalation Aerosol unit each time you refill your
prescription. This is done to assure optimal working order of the unique Azmacort Inhalation
Aerosol spacer device/delivery system. In addition, a new Azmacort Inhalation Aerosol will
guard against a build-up of the drug on the barrel portion of the device, maximizing the
cleanliness of your unit. The cost of Azmacort Inhalation Aerosol is MINIMALLY affected
by including a new inhaler with each prescription.
STORING YOUR AZMACORT INHALATION AEROSOL INHALER
•
Keep your inhaler out of the reach of children, unless otherwise prescribed.
•
Store your Azmacort Inhalation Aerosol, including the metal canister, at room temperature.
•
Protect from freezing temperatures and direct sunlight.
•
For best results, the canister should be at room temperature before use.
•
DO NOT use after the date shown as “EXP” on the label or box.
•
Azmacort Inhalation Aerosol canisters are for use with Azmacort Inhalation Aerosol
actuators and spacer-mouthpieces only. The actuator and spacer-mouthpiece should not be
used with other aerosol medications.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 15
•
REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT
give this medicine to anyone else.
DAILY CARE OF YOUR AZMACORT INHALATION AEROSOL INHALER
Your Azmacort Inhalation Aerosol MUST be cleaned in lukewarm water only once each day to
avoid build-up of medication particles in the inhaler that can block the puff of medication and
interfere with proper operation. The use of soap, detergents, or disinfectants is unnecessary.
1. IMPORTANT: Remove metal canister from inhaler. Pull canister straight out from
inhaler and place aside. Canister must be removed for proper cleaning of inhaler.
2. Pull apart remaining two plastic parts of inhaler, remove mouthpiece cap, and gently wash in
lukewarm water.
Dry thoroughly.
3. Snap the two plastic parts of the inhaler back together; push closed. Replace mouthpiece cap.
Reinsert metal canister by gently turning while inserting. The canister should fit snugly
without falling out.
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Page 16
HOW TO CHECK CONTENTS OF YOUR CANISTER
Shaking the canister will NOT give you a good estimate of how much Azmacort® (triamcinolone
acetonide) Inhalation Aerosol is left.
We have included a convenient check-off chart to assist you in keeping track of medication puffs
used. This will help assure that you receive the 240 “Full Puffs” of medication present.
Azmacort® Inhalation Aerosol 240 Puff Check-Off
•
Retain with medication or affix to convenient location.
•
Starting with puff #1, check off one circle for each puff used.
•
DISCARD MEDICATION AFTER 240 PUFFS.
FURTHER INFORMATION
•
This leaflet does not contain the complete information about your medication.
•
If you have any further questions, or are not sure about something, you should ask your
doctor or pharmacist.
•
You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you
have finished this canister.
Rx only
Aventis Pharmaceuticals Inc.
Bridgewater, NJ 08807 USA
©2002 Aventis Pharmaceuticals Inc.
Rev. May 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:37.382764
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18117slr033_azmacort_lbl.pdf', 'application_number': 18117, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
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Rev. September 2002
Rx only
Azmacort®
(triamcinolone acetonide)
Inhalation Aerosol
For Oral Inhalation Only
Shake Well Before Using
DESCRIPTION
Triamcinolone acetonide, USP, the active ingredient in Azmacort® Inhalation Aerosol, is a
corticosteroid with a molecular weight of 434.5 and with the chemical designation 9-Fluoro-
11ß,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone.
(C24H31FO6).
Azmacort Inhalation Aerosol is a metered-dose aerosol unit containing a microcrystalline
suspension of triamcinolone acetonide in the propellant dichlorodifluoromethane and dehydrated
alcohol USP 1% w/w. Each canister contains 60 mg triamcinolone acetonide. The canister must
be primed prior to the first use. After an initial priming of 2 actuations, each actuation delivers
200 mcg triamcinolone acetonide from the valve and 100 mcg from the spacer-mouthpiece under
defined in vitro test conditions. The canister will remain primed for 3 days. If the canister is not
used for more than 3 days, then it should be reprimed with 2 actuations. There are at least 240
actuations in one Azmacort Inhalation Aerosol canister. After 240 actuations, the amount
delivered per actuation may not be consistent and the unit should be discarded.
CLINICAL PHARMACOLOGY
Triamcinolone acetonide is a more potent derivative of triamcinolone. Although triamcinolone
itself is approximately one to two times as potent as prednisone in animal models of
inflammation, triamcinolone acetonide is approximately 8 times more potent than prednisone.
The precise mechanism of the action of glucocorticoids in asthma is unknown. However, the
inhaled route makes it possible to provide effective local anti-inflammatory activity with reduced
systemic corticosteroid effects. Though highly effective for asthma, glucocorticoids do not affect
asthma symptoms immediately. While improvement in asthma may occur as soon as one week
after initiation of Azmacort Inhalation Aerosol therapy, maximum improvement may not be
achieved for 2 weeks or longer.
Based upon intravenous dosing of triamcinolone acetonide phosphate ester, the half-life of
triamcinolone acetonide was reported to be 88 minutes. The volume of distribution (Vd) reported
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Page 2
was 99.5 L (SD ± 27.5) and clearance was 45.2 L/hour (SD ± 9.1) for triamcinolone acetonide.
The plasma half-life of glucocorticoids does not correlate well with the biologic half-life.
The pharmacokinetics of radiolabeled triamcinolone acetonide [14C] were evaluated following a
single oral dose of 800 mcg to healthy male volunteers. Radiolabeled triamcinolone acetonide
was found to undergo relatively rapid absorption following oral administration with maximum
plasma triamcinolone acetonide and [14C]-derived radioactivity occurring between 1.5 and 2
hours. Plasma protein binding of triamcinolone acetonide appears to be relatively low and
consistent over a wide plasma triamcinolone acetonide concentration range as a function of time.
The overall mean percent fraction bound was approximately 68%.
The metabolism and excretion of triamcinolone acetonide were both rapid and extensive with no
parent compound being detected in the plasma after 24 hours post-dose and a low ratio (10.6%)
of parent compound AUC0-∞ to total [14C] radioactivity AUC0-∞. Greater than 90% of the oral
[14C]-radioactive dose was recovered within 5 days after administration in 5 out of the 6 subjects
in the study. Of the recovered [14C]-radioactivity, approximately 40% and 60% were found in the
urine and feces, respectively.
Three metabolites of triamcinolone acetonide have been identified. They are 6ß-
hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6ß-
hydroxytriamcinolone acetonide. All three metabolites are expected to be substantially less
active than the parent compound due to (a) the dependence of anti-inflammatory activity on the
presence of a 21-hydroxyl group, (b) the decreased activity observed upon 6-hydroxylation, and
(c) the markedly increased water solubility favoring rapid elimination. There appeared to be
some quantitative differences in the metabolites among species. No differences were detected in
metabolic pattern as a function of route of administration.
CLINICAL TRIALS
Double-blind, placebo-controlled efficacy and safety studies have been conducted in asthma
patients with a range of asthma severities, from those patients with mild disease to those with
severe disease requiring oral steroid therapy.
The efficacy and safety of Azmacort Inhalation Aerosol given twice daily was demonstrated in
two placebo-controlled clinical trials. In two separate studies, 222 asthmatic patients were
randomized to receive either Azmacort Inhalation Aerosol 400 mcg twice daily or matching
placebo for a treatment period of 6 weeks. Patients were adult asthmatics who were using inhaled
beta2-agonists on more than an occasional basis (at least three times weekly), either without or
with inhaled corticosteroids, for control of their asthma symptoms. For the combined studies,
48% (52/109) patients randomized to placebo and 41% (46/113) patients randomized to
Azmacort treatment were previously treated with inhaled corticosteroids.
Results of weekly lung function tests (FEV1) from one of these trials is presented graphically
below. Results of the second study are presented in tabular form as the changes in asthma
measures from baseline to the end of the treatment period.
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Mean Changes in Asthma Measures from Baseline to Endpointa
All-Treated Patients
Results from a Placebo-Controlled, 6 Week Study
Asthma Measure
Placebo
(N=61)
Azmacort 400 mcg bid
(N=60)
Percent Change in FEV1(%)
2.8%
17.5%
Increase in Morning Peak
Flow Rate (L/min)
6.7
45.9
Decrease in Albuterol Use
(puffs/day)
0.6
3.4
Decrease in Daily Asthma Symptom
Score (units/day)b
0.5
2.3
aEndpoint Results are obtained from the last evaluable data, regardless of whether the patient completed 6 weeks of
treatment
bScale (0-6) with 0 = no symptom: Maximum Score (AM + PM) =12
In both studies, treatment with Azmacort Inhalation Aerosol (400 mcg twice daily) resulted in
significant improvements in all clinical asthma measures (lung functions, asthma symptoms, use
of as-needed beta2-agonist medications) when compared to placebo.
INDICATIONS
Azmacort Inhalation Aerosol is indicated in the maintenance treatment of asthma as
prophylactic therapy. Azmacort Inhalation Aerosol is also indicated for asthma patients who
require systemic corticosteroid administration, where adding Azmacort may reduce or eliminate
the need for the systemic corticosteroids.
Azmacort Inhalation Aerosol is NOT indicated for the relief of acute bronchospasm.
CONTRAINDICATIONS
Azmacort Inhalation Aerosol is contraindicated in the primary treatment of status asthmaticus or
other acute episodes of asthma where intensive measures are required.
Hypersensitivity to triamcinolone acetonide or any of the other ingredients in this preparation
contraindicates its use.
WARNINGS
Particular care is needed in patients who are transferred from systemically active corticosteroids
to Azmacort Inhalation Aerosol because deaths due to adrenal insufficiency have occurred in
asthmatic patients during and after transfer from systemic corticosteroids to aerosolized steroids
in recommended doses. After withdrawal from systemic corticosteroids, a number of months is
usually required for recovery of hypothalamic-pituitary-adrenal (HPA) function. For some
patients who have received large doses of oral steroids for long periods of time before therapy
with Azmacort Inhalation Aerosol is initiated, recovery may be delayed for one year or longer.
During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal
insufficiency when exposed to trauma, surgery, or infections, particularly gastroenteritis or other
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Page 4
conditions with acute electrolyte loss. Although Azmacort Inhalation Aerosol may provide
control of asthmatic symptoms during these episodes, in recommended doses it supplies only
normal physiological amounts of corticosteroid systemically and does NOT provide the
increased systemic steroid which is necessary for coping with these emergencies.
During periods of stress or a severe asthmatic attack, patients who have been recently withdrawn
from systemic corticosteroids should be instructed to resume systemic steroids (in large doses)
immediately and to contact their physician for further instruction. These patients should also be
instructed to carry a warning card indicating that they may need supplementary systemic steroids
during periods of stress or a severe asthma attack.
Localized infections with Candida albicans have occurred infrequently in the mouth and
pharynx. These areas should be examined by the treating physician at each patient visit. The
percentage of positive mouth and throat cultures for Candida albicans did not change during a
year of continuous therapy. The incidence of clinically apparent infection is low (2.5%). These
infections may disappear spontaneously or may require treatment with appropriate antifungal
therapy or discontinuance of treatment with Azmacort Inhalation Aerosol.
Children who are on immunosuppressant drugs are more susceptible to infections than healthy
children. Chickenpox and measles, for example, can have a more serious or even fatal course in
children on immunosuppressant doses of corticosteroids. In such children, or in adults who have
not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy
with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as
appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be
considered.
Azmacort Inhalation Aerosol is not to be regarded as a bronchodilator and is not indicated for
rapid relief of bronchospasm.
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase
in wheezing following dosing. If bronchospasm occurs following use of Azmacort Inhalation
Aerosol, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment
with Azmacort Inhalation Aerosol should be discontinued and alternative treatment should be
instituted.
Patients should be instructed to contact their physician immediately when episodes of asthma
which are not responsive to bronchodilators occur during the course of treatment with Azmacort
Inhalation Aerosol. During such episodes, patients may require therapy with systemic
corticosteroids.
The use of Azmacort Inhalation Aerosol with systemic prednisone, dosed either daily or on
alternate days, could increase the likelihood of HPA suppression compared to a therapeutic dose
of either one alone. Therefore, Azmacort Inhalation Aerosol should be used with caution in
patients already receiving prednisone treatment for any disease.
Transfer of patients from systemic steroid therapy to Azmacort Inhalation Aerosol may unmask
allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis,
conjunctivitis, and eczema.
PRECAUTIONS
During withdrawal from oral steroids, some patients may experience symptoms of systemically
active steroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite
maintenance or even improvement of respiratory function. (See DOSAGE AND
ADMINISTRATION.) Although steroid withdrawal effects are usually transient and not severe,
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severe and even fatal exacerbation of asthma can occur if the previous daily oral corticosteroid
requirement had significantly exceeded 10 mg/day of prednisone or equivalent.
In responsive patients, inhaled corticosteroids will often permit control of asthmatic symptoms
with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.
Since triamcinolone acetonide is absorbed into the circulation and can be systemically active, the
beneficial effects of Azmacort Inhalation Aerosol in minimizing or preventing HPA dysfunction
may be expected only when recommended dosages are not exceeded.
Suppression of HPA function has been reported in volunteers who received 4000 mcg daily of
triamcinolone acetonide by oral inhalation. In addition, suppression of HPA function has been
reported in some patients who have received recommended doses for as little as 6 to 12 weeks.
Since the response of HPA function to inhaled corticosteroids is highly individualized, the
physician should consider this information when treating patients.
When used at excessive doses or at recommended doses in a small number of susceptible
individuals, systemic corticosteroid effects such as hypercorticoidism and adrenal suppression
may appear. If such changes occur, Azmacort® (triamcinolone acetonide) Inhalation Aerosol
should be discontinued slowly, consistent with accepted procedures for reducing systemic steroid
therapy and for management of asthma symptoms.
Azmacort Inhalation Aerosol should be used with caution, if at all, in patients with active or
quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial,
parasitic, or viral infections; or ocular herpes simplex.
The long-term local and systemic effects of Azmacort Inhalation Aerosol in human subjects are
still not fully known. While there has been no clinical evidence of adverse experiences, the
effects resulting from chronic use of Azmacort Inhalation Aerosol on developmental or
immunologic processes in the mouth, pharynx, trachea, and lung are unknown.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with
these drugs should be observed carefully for any evidence of systemic corticosteroid effects
including suppression of growth in children. Particular care should be taken in observing patients
postoperatively or during periods of stress for evidence of a decrease in adrenal function.
Information for Patients: Patients being treated with Azmacort Inhalation Aerosol should
receive the following information and instructions. This information is intended to aid them in
the safe and effective use of this medication. It is not a complete disclosure of all possible
adverse or intended effects.
Patients should use Azmacort Inhalation Aerosol at regular intervals as directed. Results of
clinical trials indicate that significant improvement in asthma may occur by 1 week, but
maximum benefit may not be achieved for 2 weeks or more. The patient should not increase the
prescribed dosage but should contact the physician if symptoms do not improve or if the
condition worsens.
In clinical studies and post-marketing experience with Azmacort Inhalation Aerosol, local
infections of the oropharynx with Candida albicans have occurred. When such an infection
develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy
while remaining on treatment with Azmacort Inhalation Aerosol. However, at times therapy
with Azmacort Inhalation Aerosol may need to be interrupted.
Patients should be instructed to track their use of Azmacort Inhalation Aerosol and to dispose of
the canister after 240 actuations since reliable dose delivery cannot be assured after 240 doses.
Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid
exposure to chickenpox or measles and, if exposed, to obtain medical advice.
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Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of treatment-related
carcinogenicity was demonstrated after two years of once daily gavage of triamcinolone
acetonide at doses of 0.05, 0.2, and 1.0 mcg/kg (approximately 0.02, 0.07, and 0.4% of the
maximum recommended human daily inhalation dose on a mcg/m2 basis) in the rat and 0.1, 0.6,
and 3.0 mcg/kg (approximately 0.02, 0.1, and 0.6% of the maximum recommended human daily
inhalation dose on a mcg/m2 basis) in a mouse.
Mutagenesis studies with triamcinolone acetonide have not been carried out.
No evidence of impaired fertility was manifested when oral doses of up to 15.0 mcg/kg (8% of
the maximum recommended human daily inhalation dose on a mcg/m2 basis) were administered
to female and male rats. However, triamcinolone acetonide at oral doses of 8 mcg/kg
(approximately 4% of the maximum recommended human daily inhalation dose on a mcg/m2
basis) caused dystocia and prolonged delivery and at oral doses of 5.0 mcg/kg (approximately
2.5% of the maximum recommended human daily inhalation dose on a mcg/m2 basis) and above
caused increases in fetal resorptions and stillbirths and decreases in pup body weight and
survival. At a lower dose of 1.0 mcg/kg (approximately 0.5% of the maximum recommended
human daily inhalation dose on a mcg/m2 basis) it did not induce the above mentioned effects.
Pregnancy: Pregnancy Category C. Triamcinolone acetonide has been shown to be teratogenic
at inhalational doses of 20, 40, and 80 mcg/kg in rats (approximately 0.1, 0.2, and 0.4 times the
maximum recommended human daily inhalation dose on a mcg/m2 basis, respectively), in rabbits
at the same doses (approximately 0.2, 0.4, and 0.8 times the maximum recommended human
daily inhalation dose on a mcg/m2 basis, respectively) and in monkeys, at an inhalational dose of
500 mcg/kg (approximately 5 times the maximum recommended human daily inhalation dose on
a mcg/m2 basis). Dose related teratogenic effects in rats and rabbits included cleft palate and/or
internal hydrocephaly and axial skeletal defects whereas the teratogenic effects observed in the
monkey were CNS and/or cranial malformations. There are no adequate and well controlled
studies in pregnant women. Triamcinolone acetonide should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Experience with oral glucocorticoids since their introduction in pharmacologic as opposed to
physiologic doses suggests that rodents are more prone to teratogenic effects from
glucocorticoids than humans. In addition, because there is a natural increase in glucocorticoid
production during pregnancy, most women will require a lower exogenous steroid dose and
many will not need glucocorticoid treatment during pregnancy.
Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving
corticosteroids during pregnancy. Such infants should be carefully observed.
Nursing Mothers: It is not known whether triamcinolone acetonide is excreted in human milk.
Because other corticosteroids are excreted in human milk, caution should be exercised when
Azmacort Inhalation Aerosol is administered to nursing women.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients below the
age of 6. Oral corticosteroids have been shown to cause growth suppression in children and
teenagers, particularly with higher doses over extended periods. If a child or teenager on any
corticosteroid appears to have growth suppression, the possibility that they are particularly
sensitive to this effect of steroids should be considered.
ADVERSE REACTIONS
The table below describes the incidence of common adverse experiences based upon three
placebo-controlled, multicenter US clinical trials of 507 patients (297 female and 210 male
adults (age range 18-64)). These trials included asthma patients who had previously received
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Page 7
inhaled beta2-agonists alone, as well as those who previously required inhaled corticosteroid
therapy for the control of their asthma. The patients were treated with Azmacort Inhalation
Aerosol (including doses ranging from 200 to 800 mcg twice daily for 6 weeks) or placebo.
Adverse Events Occurring at an Incidence of Greater Than 3%
and Greater Than Placebo
Adverse Event
Azmacort Dose
Placebo
200 mcg bid
(n=57)
400 mcg bid
(n=170)
800 mcg bid
(n=57)
(n=167)
Sinusitis
5 (9%)
7 (4%)
1 (2%)
6 (4%)
Pharyngitis
4 (7%)
42 (25%)
10 (18%)
19 (11%)
Headache
4 (7%)
35 (21%)
7 (12%)
24 (14%)
Flu Syndrome
2 (4%)
8 (5%)
1 (2%)
5 (3%)
Back Pain
2 (4%)
3 (2%)
2 (4%)
3 (2%)
Adverse events that occurred at an incidence of 1-3% in the overall Azmacort Inhalation
Aerosol treatment group and greater than placebo included:
Body as a whole:
facial edema, pain, abdominal pain, photosensitivity
Digestive system:
diarrhea, oral monilia, toothache, vomiting
Metabolic and Nutrition:
weight gain
Musculoskeletal system:
bursitis, myalgia, tenosynovitis
Nervous system:
dry mouth
Organs of special sense:
rash
Respiratory system:
chest congestion, voice alteration
Urogenital system:
cystitis, urinary tract infection, vaginal monilia
In older controlled clinical trials of steroid dependent asthmatics, urticaria was reported rarely.
Anaphylaxis was not reported in these controlled trials. Typical steroid withdrawal effects
including muscle aches, joint aches, and fatigue were noted in clinical trials when patients were
transferred from oral steroid therapy to Azmacort Inhalation Aerosol. Easy bruisability was also
noted in these trials.
Hoarseness, dry throat, irritated throat, dry mouth, facial edema, increased wheezing, and cough
have been reported. These adverse effects have generally been mild and transient. Cases of oral
candidiasis occurring with clinical use have been reported. (See WARNINGS.)
Post Marketing: In addition to adverse events reported from clinical trials, the following events
have been reported post marketing: identified during post approval use of AZMACORT where
these events were reported voluntarily from a population of unknown size, and the frequency of
occurrence cannot be determined precisely. These include rare reports of anaphylaxis, cataracts,
and glaucoma.
OVERDOSAGE
There are no data available on the effects of acute or chronic overdose. However, acute
overdosing with Azmacort Inhalation Aerosol is unlikely in view of the total amount of active
ingredient present and the route of administration. The maximum total daily dose (1600 mcg) has
been well tolerated when administered as a single dose of 16 consecutive inhalations to adult
asthmatics in a controlled clinical trial. Chronic overdosage may result in signs/symptoms of
hypercorticoidism. (See PRECAUTIONS.) The risk of candidiasis could also be increased.
DOSAGE AND ADMINISTRATION
Adults: The usual recommended dosage is two inhalations (200 mcg) given three to four times a
day or four inhalations (400 mcg) given twice daily. The maximal daily intake should not exceed
16 inhalations (1600 mcg) in adults. Higher initial doses (12 to 16 inhalations per day) may be
considered in patients with more severe asthma.
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Children 6 to 12 Years of Age: The usual recommended dosage is one or two inhalations (100
to 200 mcg) given three to four times a day or two to four inhalations (200 to 400 mcg) given
twice daily. The maximal daily intake should not exceed 12 inhalations (1200 mcg) in children 6
to 12 years of age. Insufficient clinical data exist with respect to the safety and efficacy of the
administration of Azmacort Inhalation Aerosol to children below the age of 6. The long-term
effects of inhaled steroids, including Azmacort Inhalation Aerosol, on growth are still not fully
known.
Rinsing the mouth after inhalation is advised.
Different considerations must be given to the following groups of patients in order to obtain the
full therapeutic benefit of Azmacort Inhalation Aerosol:
Note: In all patients, it is desirable to titrate to the lowest effective dose once asthma
stability has been achieved.
Patients Not Receiving Systemic Corticosteroids: Patients who require maintenance therapy of
their asthma may benefit from treatment with Azmacort Inhalation Aerosol at the doses
recommended above. In patients who respond to Azmacort Inhalation Aerosol, improvement in
pulmonary function is usually apparent within one to two weeks after the initiation of therapy.
Patients Maintained on Systemic Corticosteroids: Clinical studies have shown that Azmacort
Inhalation Aerosol may be effective in the management of asthmatics dependent or maintained
on systemic corticosteroids and may permit replacement or significant reduction in the dosage of
systemic corticosteroids.
The patient’s asthma should be reasonably stable before treatment with Azmacort Inhalation
Aerosol is started. Initially, Azmacort Inhalation Aerosol should be used concurrently with the
patient’s usual maintenance dose of systemic corticosteroid. After approximately one week,
gradual withdrawal of the systemic corticosteroid is started by reducing the daily or alternate
daily dose. Reductions may be made after an interval of one or two weeks, depending on the
response of the patient. A slow rate of withdrawal is strongly recommended. Generally, these
decrements should not exceed 2.5 mg of prednisone or its equivalent. During withdrawal, some
patients may experience symptoms of systemic corticosteroid withdrawal, e.g., joint and/or
muscular pain, lassitude, and depression, despite maintenance or even improvement in
pulmonary function. Such patients should be encouraged to continue with the inhaler but should
be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency
occurs, the systemic corticosteroid doses should be increased temporarily and thereafter
withdrawal should continue more slowly. Inhaled corticosteroids should be used with caution
when used chronically in patients receiving prednisone regimens, either daily or alternate day.
(See WARNINGS.)
During periods of stress or a severe asthma attack, transfer patients may require supplementary
treatment with systemic corticosteroids.
Directions for Use: An illustrated leaflet of patient instructions for proper use accompanies each
package of Azmacort Inhalation Aerosol.
HOW SUPPLIED
Azmacort Inhalation Aerosol contains 60 mg triamcinolone acetonide in a 20 gram package
which delivers at least 240 actuations. It is supplied with a white plastic actuator, a white plastic
spacer-mouthpiece and patient’s leaflet of instructions: box of one. NDC 0075-0060-37. Each
actuation delivers 200 mcg triamcinolone acetonide from the valve and 100 mcg from the spacer-
mouthpiece under defined in vitro test conditions.
Avoid spraying in eyes.
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For best results, the canister should be at room temperature before use.
Shake well before using.
CONTENTS UNDER PRESSURE. Do not puncture. Do not use or store near heat or open
flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire
or incinerator. Keep out of reach of children unless otherwise prescribed. Store at Controlled
Room Temperature 20 to 25°C (68 to 77°F) [see USP].
Note: The indented statement below is required by the Federal government’s Clean Air Act for
all products containing or manufactured with chlorofluorocarbons (CFCs):
WARNING: Contains CFC-12, a substance which harms public health and the environment
by destroying ozone in the upper atmosphere.
A notice similar to the above WARNING has been placed in the “Information For The Patient”
portion of this package insert under the Environmental Protection Agency’s (EPA’s) regulations.
The patient’s warning states that the patient should consult his or her physician if there are
questions about alternatives.
Rx only
Aventis Pharmaceuticals Inc.
Bridgewater, NJ 08807 USA
©2002 Aventis Pharmaceuticals Inc.
Rev. September 2002
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INFORMATION FOR THE PATIENT
Your Guide to the
Special Delivery System
Your doctor has prescribed Azmacort® (triamcinolone acetonide) Inhalation Aerosol to help
control your asthma. Your Azmacort Inhalation Aerosol is one of the most efficient and easy-to-
use devices available to help you take your prescribed medication. Used properly, it will
effectively and reliably relieve your asthma symptoms.
To receive the maximum benefit, it is very important that you carefully read and follow all
the instructions contained in this booklet for the daily use and care of your Azmacort
Inhalation Aerosol.
IMPORTANT NOTE: If you’ve used other metered-dose inhalers before, you may expect the
Azmacort Inhalation Aerosol to deliver a noticeable “blast” of medication into your mouth.
Your AZMACORT Inhalation Aerosol, however, is designed to provide a gentle mist, not a
“blast,” when used.
This gentle action makes it possible for your medication to be more effectively delivered into the
passageways to your lungs, with very little left to linger in your mouth. In fact, you may not even
feel the medication entering your mouth, but rest assured, that is how the Azmacort Inhalation
Aerosol works.
IMPORTANT: Please read all instructions in this guide carefully before using your Azmacort
Inhalation Aerosol.
BEFORE STARTING TO TAKE THIS MEDICINE, TELL YOUR DOCTOR:
•
If you are pregnant or intending to become pregnant.
•
If you are breast-feeding a baby.
•
If you are allergic to Azmacort Inhalation Aerosol or any other orally inhaled glucocorticoid.
•
If you are taking other medications. In some circumstances, this medication may not be
suitable and your doctor may wish to give you a different medicine.
PREPARE YOUR AZMACORT INHALATION AEROSOL
INHALER FOR USE
STEP 1
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1. Line up the arrows on the inhaler.
STEP 2
2. Gently pull the inhaler to its fully extended position. You will see the valve (small hole)
where the medication will come out.
STEP 3
3. Adjust the inhaler into an “L” shape. It is hinged to swing in one direction only.
STEP 4
4. The ridge on the top part of the inhaler should fit into the notch on the bottom part.
STEP 5
5. Remove the mouthpiece cap. To prepare your Azmacort Inhalation Aerosol for use, the
inhaler must be primed prior to the first use. To prime, hold the inhaler upright, with the
mouthpiece facing away from you. Shake the inhaler gently, then press the canister firmly
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and quickly. Repeat this procedure again so a total of 2 puffs are released. Your Azmacort
Inhalation Aerosol is now ready for use.
Repriming is only necessary when your inhaler has not been used for more than 3 days. To
reprime, shake the inhaler and release one puff. Repeat this procedure again so a total of two
puffs are released.
USING YOUR AZMACORT INHALATION AEROSOL INHALER
STEP 6
6. The metal Azmacort canister has already been inserted into the inhaler. Once you have
opened the inhaler, shake it well before each use. IMPORTANT: You must shake the
inhaler each and every time before inhaling the medication. If your doctor has instructed
you to take more than one breath of medication at a time, you must shake the inhaler
EACH TIME before each inhalation of medication, NOT JUST ONCE.
STEP 7
7. Breathe out to empty your lungs completely before using the inhaler! This is important to
make sure that you can breathe the medication deeply into your lungs.
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STEP 8
8. Place mouthpiece into your mouth, and close your lips tightly around it. Press down firmly
and steadily on the metal canister while breathing in slowly and deeply THROUGH YOUR
MOUTH ONLY. (If necessary, pinch your nose closed.) Be sure to release your finger
pressure from the top of the canister after the medication is released.
Remember, the Azmacort Inhalation Aerosol delivers a gentle mist of medication, so don’t
be surprised if you hardly feel it.
Do not remove the inhaler from your mouth after breathing in the medication. Hold
your breath for 10 seconds with the inhaler STILL in your mouth, THEN remove the
inhaler and breathe out very slowly.
Unlike the other inhalers you may have used, you will not feel the medication impact the
back of your mouth. This is because of the unique design of the Azmacort Inhalation Aerosol
delivery system.
STEP 9
9. If your doctor has told you to take more than one breath of medication at a time: WAIT AT
LEAST 60 SECONDS between each one, then start again at Step 6.
STEP 10
10. After the prescribed number of inhalations, thoroughly rinse out your mouth with water.
NOTE: If your mouth becomes sore or develops a rash, be sure to mention this to your
physician, but do not stop using your inhaler unless instructed to do so.
DOSAGE: USE ONLY AS DIRECTED BY YOUR PHYSICIAN
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WARNING: Azmacort® (triamcinolone acetonide) Inhalation Aerosol contains medication that
is intended for treatment of your asthma. It does not contain medication intended to provide rapid
relief of your breathing difficulties during an asthma attack.
It is very important that you use Azmacort Inhalation Aerosol regularly at the intervals
recommended by your doctor, and not as an emergency measure. Your physician will decide
whether other medication is needed, should you require immediate relief.
CAUTION: CONTENTS OF CANISTER UNDER PRESSURE.
Do not puncture. Do not store near heat or open flame. Exposure to temperatures above 120°F
may cause bursting. Never throw canisters into a fire or incinerator. Please keep out of the reach
of children.
Note: The indented statement below is required by the Federal government’s Clean Air Act for
all products containing or manufactured with chlorofluorocarbons (CFCs):
This product contains CFC-12, a substance which harms the environment by destroying ozone
in the upper atmosphere.
Your physician has determined that this product is likely to help your personal health. USE
THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY
YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.
IMPORTANT TIPS FOR USING YOUR AZMACORT INHALATION AEROSOL
INHALER
•
Always use only as directed by your physician. Do not use it more often than instructed; do
not skip doses.
•
Follow all instructions in this booklet very closely and carefully for best results, especially
those for use and cleaning.
•
Remember, repriming is only necessary when the inhaler has not been used for more than 3
days. To reprime, shake the inhaler gently and release one puff. Repeat this procedure again
so that a total of two puffs have been released. Do not reprime between more frequent usage.
•
Please Note:
You will receive a new Azmacort Inhalation Aerosol unit each time you refill your
prescription. This is done to assure optimal working order of the unique Azmacort Inhalation
Aerosol spacer device/delivery system. In addition, a new Azmacort Inhalation Aerosol will
guard against a build-up of the drug on the barrel portion of the device, maximizing the
cleanliness of your unit. The cost of Azmacort Inhalation Aerosol is MINIMALLY affected
by including a new inhaler with each prescription.
STORING YOUR AZMACORT INHALATION AEROSOL INHALER
•
Keep your inhaler out of the reach of children, unless otherwise prescribed.
•
Store your Azmacort Inhalation Aerosol, including the metal canister, at room temperature.
•
Protect from freezing temperatures and direct sunlight.
•
For best results, the canister should be at room temperature before use.
•
DO NOT use after the date shown as “EXP” on the label or box.
•
Azmacort Inhalation Aerosol canisters are for use with Azmacort Inhalation Aerosol
actuators and spacer-mouthpieces only. The actuator and spacer-mouthpiece should not be
used with other aerosol medications.
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Page 15
•
REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT
give this medicine to anyone else.
DAILY CARE OF YOUR AZMACORT INHALATION AEROSOL INHALER
Your Azmacort Inhalation Aerosol MUST be cleaned in lukewarm water only once each day to
avoid build-up of medication particles in the inhaler that can block the puff of medication and
interfere with proper operation. The use of soap, detergents, or disinfectants is unnecessary.
1. IMPORTANT: Remove metal canister from inhaler. Pull canister straight out from
inhaler and place aside. Canister must be removed for proper cleaning of inhaler.
2. Pull apart remaining two plastic parts of inhaler, remove mouthpiece cap, and gently wash in
lukewarm water.
Dry thoroughly.
3. Snap the two plastic parts of the inhaler back together; push closed. Replace mouthpiece cap.
Reinsert metal canister by gently turning while inserting. The canister should fit snugly
without falling out.
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Page 16
HOW TO CHECK CONTENTS OF YOUR CANISTER
Shaking the canister will NOT give you a good estimate of how much Azmacort® (triamcinolone
acetonide) Inhalation Aerosol is left.
We have included a convenient check-off chart to assist you in keeping track of medication puffs
used. This will help assure that you receive the 240 “Full Puffs” of medication present.
Azmacort® Inhalation Aerosol 240 Puff Check-Off
•
Retain with medication or affix to convenient location.
•
Starting with puff #1, check off one circle for each puff used.
•
DISCARD MEDICATION AFTER 240 PUFFS.
FURTHER INFORMATION
•
This leaflet does not contain the complete information about your medication.
•
If you have any further questions, or are not sure about something, you should ask your
doctor or pharmacist.
•
You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you
have finished this canister.
Rx only
Aventis Pharmaceuticals Inc.
Bridgewater, NJ 08807 USA
©2002 Aventis Pharmaceuticals Inc.
Rev. September 2002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:37.437909
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18117slr032_azmacort_lbl.pdf', 'application_number': 18117, 'submission_type': 'SUPPL ', 'submission_number': 32}
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11,167
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1
ATIVAN (lorazepam) Injection
Rx only
DESCRIPTION
Lorazepam, a benzodiazepine with antianxiety, sedative, and anticonvulsant effects, is
intended for the intramuscular or intravenous routes of administration. It has the
chemical formula: 7-chloro-5(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,
4-benzodiazepin-2-one. The molecular weight is 321.16, and the C.A.S. No. is
[846-49-1]. The structural formula is:
Lorazepam is a nearly white powder almost insoluble in water. Each mL of sterile
injection contains either 2.0 or 4.0 mg of lorazepam, 0.18 mL polyethylene glycol 400 in
propylene glycol with 2.0% benzyl alcohol as preservative.
CLINICAL PHARMACOLOGY
Lorazepam interacts with the γ-aminobutyric acid (GABA)-benzodiazepine receptor
complex, which is widespread in the brain of humans as well as other species. This
interaction is presumed to be responsible for lorazepam’s mechanism of action.
Lorazepam exhibits relatively high and specific affinity for its recognition site but does
not displace GABA. Attachment to the specific binding site enhances the affinity of
GABA for its receptor site on the same receptor complex. The pharmacodynamic
consequences of benzodiazepine agonist actions include antianxiety effects, sedation, and
reduction of seizure activity. The intensity of action is directly related to the degree of
benzodiazepine receptor occupancy.
Effects in Pre-Operative Patients
Intravenous or intramuscular administration of the recommended dose of 2 mg to 4 mg of
ATIVAN Injection to adult patients is followed by dose-related effects of sedation
(sleepiness or drowsiness), relief of preoperative anxiety, and lack of recall of events
related to the day of surgery in the majority of patients. The clinical sedation (sleepiness
or drowsiness) thus noted is such that the majority of patients are able to respond to
simple instructions whether they give the appearance of being awake or asleep. The lack
of recall is relative rather than absolute, as determined under conditions of careful patient
questioning and testing, using props designed to enhance recall. The majority of patients
under these reinforced conditions had difficulty recalling perioperative events or
recognizing props from before surgery. The lack of recall and recognition was optimum
within 2 hours following intramuscular administration and 15 to 20 minutes after
intravenous injection.
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The intended effects of the recommended adult dose of ATIVAN Injection usually last 6
to 8 hours. In rare instances, and where patients received greater than the recommended
dose, excessive sleepiness and prolonged lack of recall were noted. As with other
benzodiazepines, unsteadiness, enhanced sensitivity to CNS-depressant effects of ethyl
alcohol and other drugs were noted in isolated and rare cases for greater than 24 hours.
Physiologic Effects in Healthy Adults
Studies in healthy adult volunteers reveal that intravenous lorazepam in doses up to
3.5 mg/70 kg does not alter sensitivity to the respiratory stimulating effect of carbon
dioxide and does not enhance the respiratory-depressant effects of doses of
meperidine up to 100 mg/70 kg (also determined by carbon dioxide challenge) as
long as patients remain sufficiently awake to undergo testing. Upper airway
obstruction has been observed in rare instances where the patient received greater
than the recommended dose and was excessively sleepy and difficult to arouse (see
WARNINGS and ADVERSE REACTIONS).
Clinically employed doses of ATIVAN Injection do not greatly affect the circulatory
system in the supine position or employing a 70-degree tilt test. Doses of 8 mg to 10 mg
of intravenous lorazepam (2 to 2-1/2 times the maximum recommended dosage) will
produce loss of lid reflexes within 15 minutes.
Studies in 6 healthy young adults who received lorazepam injection and no other drugs
revealed that visual tracking (the ability to keep a moving line centered) was impaired for
a mean of 8 hours following administration of 4 mg of intramuscular lorazepam and 4
hours following administration of 2 mg intramuscularly with considerable subject
variation. Similar findings were noted with pentobarbital, 150 and 75 mg. Although this
study showed that both lorazepam and pentobarbital interfered with eye-hand
coordination, the data are insufficient to predict when it would be safe to operate a motor
vehicle or engage in a hazardous occupation or sport.
Pharmacokinetics and Metabolism
Absorption
Intravenous
A 4-mg dose provides an initial concentration of approximately 70 ng/mL.
Intramuscular
Following intramuscular administration, lorazepam is completely and rapidly absorbed
reaching peak concentrations within 3 hours. A 4-mg dose provides a Cmax of
approximately 48 ng/mL. Following administration of 1.5 to 5.0 mg of lorazepam IM, the
amount of lorazepam delivered to the circulation is proportional to the dose administered.
Distribution/Metabolism/Elimination
At clinically relevant concentrations, lorazepam is 91±2% bound to plasma proteins; its
volume of distribution is approximately 1.3 L/kg. Unbound lorazepam penetrates the
blood/brain barrier freely by passive diffusion, a fact confirmed by CSF sampling.
Following parenteral administration, the terminal half-life and total clearance averaged
14±5 hours and 1.1±0.4 mL/min/kg, respectively.
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3
Lorazepam is extensively conjugated to the 3-O-phenolic glucuronide in the liver and is
known to undergo enterohepatic recirculation. Lorazepam glucuronide is an inactive
metabolite and is eliminated mainly by the kidneys.
Following a single 2-mg oral dose of 14C-lorazepam to 8 healthy subjects, 88±4% of the
administered dose was recovered in urine and 7±2% was recovered in feces. The percent
of administered dose recovered in urine as lorazepam glucuronide was 74±4%. Only
0.3% of the dose was recovered as unchanged lorazepam, and the remainder of the
radioactivity represented minor metabolites.
Special Populations
Effect of Age
Pediatrics
NEONATES (BIRTH TO 1 MONTH)
Following a single 0.05 mg/kg (n=4) or 0.1 mg/kg (n=6) intravenous dose of lorazepam,
mean total clearance normalized to body weight was reduced by 80% compared to
normal adults, terminal half-life was prolonged 3-fold, and volume of distribution was
decreased by 40% in neonates with asphyxia neonatorum compared to normal adults. All
neonates were of ≥37 weeks of gestational age.
INFANTS (1 MONTH UP TO 2 YEARS)
There is no information on the pharmacokinetic profile of lorazepam in infants in the age
range of 1 month to 2 years.
CHILDREN (2 YEARS TO 12 YEARS)
Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution
(normalized to body-weight) and a 30% longer mean half-life in children with acute
lymphocytic leukemia in complete remission (2 to 12 years, n=37) compared to normal
adults (n=10). Unbound lorazepam clearance normalized to body-weight was comparable
in children and adults.
ADOLESCENTS (12 YEARS TO 18 YEARS)
Total (bound and unbound) lorazepam had a 50% higher mean volume of distribution
(normalized to body-weight) and a mean half-life that was two fold greater in adolescents
with acute lymphocytic leukemia in complete remission (12 to 18 years, n=13) compared
to normal adults (n=10). Unbound lorazepam clearance normalized to body-weight was
comparable in adolescents and adults.
Elderly
Following single intravenous doses of 1.5 to 3 mg of ATIVAN Injection, mean total body
clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age
compared to that in 15 younger subjects of 19 to 38 years of age. Consequently, no
dosage adjustment appears to be necessary in elderly subjects based solely on their age.
Effect of Gender
Gender has no effect on the pharmacokinetics of lorazepam.
Effect of Race
Young Americans (n=15) and Japanese subjects (n=7) had very comparable mean
total clearance value of 1.0 mL/min/kg. However, elderly Japanese subjects had a
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4
20% lower mean total clearance than elderly Americans, 0.59 mL/min/kg vs
0.77 mL/min/kg, respectively.
Patients With Renal Insufficiency
Because the kidney is the primary route of elimination of lorazepam glucuronide, renal
impairment would be expected to compromise its clearance. This should have no direct
effect on the glucuronidation (and inactivation) of lorazepam. There is a possibility that
the enterohepatic circulation of lorazepam glucuronide leads to a reduced efficiency of
the net clearance of lorazepam in this population.
Six normal subjects, six patients with renal impairment (Clcr of 22±9 mL/min), and four
patients on chronic maintenance hemodialysis were given single 1.5 to 3.0 mg
intravenous doses of lorazepam. Mean volume of distribution and terminal half-life
values of lorazepam were 40% and 25% higher, respectively, in renally impaired patients
than in normal subjects. Both parameters were 75% higher in patients undergoing
hemodialysis than in normal subjects. Overall, though, in this group of subjects the mean
total clearance of lorazepam did not change. About 8% of the administered intravenous
dose was removed as intact lorazepam during the 6-hour dialysis session.
The kinetics of lorazepam glucuronide were markedly affected by renal dysfunction. The
mean terminal half-life was prolonged by 55% and 125% in renally impaired patients and
patients under hemodialysis, respectively, as compared to normal subjects. The mean
metabolic clearance decreased by 75% and 90% in renally impaired patients and patients
under hemodialysis, respectively, as compared with normal subjects. About 40% of the
administered lorazepam intravenous dose was removed as glucuronide conjugate during
the 6-hour dialysis session.
Hepatic Disease
Because cytochrome oxidation is not involved with the metabolism of lorazepam, liver
disease would not be expected to have an effect on metabolic clearance. This prediction
is supported by the observation that following a single 2 mg intravenous dose of
lorazepam, cirrhotic male patients (n=13) and normal male subjects (n=11) exhibited no
substantive difference in their ability to clear lorazepam.
Effect of Smoking
Administration of a single 2 mg intravenous dose of lorazepam showed that there was no
difference in any of the pharmacokinetic parameters of lorazepam between cigarette
smokers (n=10, mean=31 cigarettes per day) and nonsmoking subjects (n=10) who were
matched for age, weight and gender.
Clinical Studies
The effectiveness of ATIVAN Injection in status epilepticus was established in two
multi-center controlled trials in 177 patients. With rare exceptions, patients were
between 18 and 65 years of age. More than half the patients in each study had
tonic-clonic status epilepticus; patients with simple partial and complex partial status
epilepticus comprised the rest of the population studied, along with a smaller number of
patients who had absence status.
One study (n=58) was a double-blind active-control trial comparing ATIVAN Injection
and diazepam. Patients were randomized to receive ATIVAN 2 mg IV (with an additional
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5
2 mg IV if needed) or diazepam 5 mg IV (with an additional 5 mg IV if needed). The
primary outcome measure was a comparison of the proportion of responders in each
treatment group, where a responder was defined as a patient whose seizures stopped
within 10 minutes after treatment and who continued seizure-free for at least an
additional 30 minutes. Twenty-four of the 30 (80%) patients were deemed responders to
ATIVAN and 16/28 (57%) patients were deemed responders to diazepam (p=0.04). Of
the 24 ATIVAN responders, 23 received both 2 mg infusions.
Non-responders to ATIVAN 4 mg were given an additional 2 to 4 mg ATIVAN;
non-responders to diazepam 10 mg were given an additional 5 to 10 mg diazepam. After
this additional dose administration, 28/30 (93%) of patients randomized to ATIVAN and
24/28 (86%) of patients randomized to diazepam were deemed responders, a difference
that was not statistically significant.
Although this study provides support for the efficacy of ATIVAN as the treatment for
status epilepticus, it cannot speak reliably or meaningfully to the comparative
performance of either diazepam (Valium) or lorazepam (ATIVAN Injection) under the
conditions of actual use.
A second study (n=119) was a double-blind dose-comparison trial with 3 doses of
ATIVAN Injection: 1 mg, 2 mg, and 4 mg. Patients were randomized to receive one of
the three doses of ATIVAN. The primary outcome and definition of responder were as in
the first study. Twenty-five of 41 patients (61%) responded to 1 mg ATIVAN; 21/37
patients (57%) responded to 2 mg ATIVAN; and 31/41 (76%) responded to 4 mg
ATIVAN. The p-value for a statistical test of the difference between the ATIVAN 4 mg
dose group and the ATIVAN 1-mg dose group was 0.08 (two-sided). Data from all
randomized patients were used in this test.
Although analyses failed to detect an effect of age, sex, or race on the effectiveness of
ATIVAN in status epilepticus, the numbers of patients evaluated were too few to allow a
definitive conclusion about the role these factors may play.
INDICATIONS AND USAGE
Status Epilepticus
ATIVAN Injection is indicated for the treatment of status epilepticus.
Preanesthetic
ATIVAN Injection is indicated in adult patients for preanesthetic medication, producing
sedation (sleepiness or drowsiness), relief of anxiety, and a decreased ability to recall
events related to the day of surgery. It is most useful in those patients who are anxious
about their surgical procedure and who would prefer to have diminished recall of the
events of the day of surgery (see PRECAUTIONS, Information for Patients).
CONTRAINDICATIONS
ATIVAN Injection is contraindicated in patients with a known sensitivity to
benzodiazepines or its vehicle (polyethylene glycol, propylene glycol, and benzyl
alcohol), in patients with acute narrow-angle glaucoma, or in patients with sleep
apnea syndrome. It is also contraindicated in patients with severe respiratory
insufficiency, except in those patients requiring relief of anxiety and/or diminished
recall of events while being mechanically ventilated. The use of ATIVAN Injection
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6
intra-arterially is contraindicated because, as with other injectable benzodiazepines,
inadvertent intra-arterial injection may produce arteriospasm resulting in gangrene
which may require amputation (see WARNINGS).
WARNINGS
Use in Status Epilepticus
Management of Status Epilepticus
Status epilepticus is a potentially life-threatening condition associated with a high risk of
permanent neurological impairment, if inadequately treated. The treatment of status,
however, requires far more than the administration of an anticonvulsant agent. It involves
observation and management of all parameters critical to maintaining vital function and
the capacity to provide support of those functions as required. Ventilatory support must
be readily available. The use of benzodiazepines, like ATIVAN Injection, is ordinarily
only one step of a complex and sustained intervention which may require additional
interventions (e.g., concomitant intravenous administration of phenytoin). Because status
epilepticus may result from a correctable acute cause such as hypoglycemia,
hyponatremia, or other metabolic or toxic derangement, such an abnormality must be
immediately sought and corrected. Furthermore, patients who are susceptible to further
seizure episodes should receive adequate maintenance antiepileptic therapy.
Any health care professional who intends to treat a patient with status epilepticus should
be familiar with this package insert and the pertinent medical literature concerning
current concepts for the treatment of status epilepticus. A comprehensive review of the
considerations critical to the informed and prudent management of status epilepticus
cannot be provided in drug product labeling. The archival medical literature contains
many informative references on the management of status epilepticus, among them the
report of the working group on status epilepticus of the Epilepsy Foundation of America
“Treatment of Convulsive Status Epilepticus” (JAMA 1993; 270:854-859). As noted in
the report just cited, it may be useful to consult with a neurologist if a patient fails to
respond (e.g., fails to regain consciousness).
For the treatment of status epilepticus, the usual recommended dose of ATIVAN
Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures
cease, no additional ATIVAN Injection is required. If seizures continue or recur after a
10- to 15- minute observation period, an additional 4 mg intravenous dose may be slowly
administered. Experience with further doses of ATIVAN is very limited. The usual
precautions in treating status epilepticus should be employed. An intravenous infusion
should be started, vital signs should be monitored, an unobstructed airway should be
maintained, and artificial ventilation equipment should be available.
Respiratory Depression
The most important risk associated with the use of ATIVAN Injection in status
epilepticus is respiratory depression. Accordingly, airway patency must be assured and
respiration monitored closely. Ventilatory support should be given as required.
Excessive Sedation
Because of its prolonged duration of action, the prescriber should be alert to the
possibility, especially when multiple doses have been given, that the sedative effects of
lorazepam may add to the impairment of consciousness seen in the post-ictal state.
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7
Preanesthetic Use
AIRWAY OBSTRUCTION MAY OCCUR IN HEAVILY SEDATED PATIENTS.
INTRAVENOUS LORAZEPAM AT ANY DOSE, WHEN GIVEN EITHER ALONE
OR IN COMBINATION WITH OTHER DRUGS ADMINISTERED DURING
ANESTHESIA, MAY PRODUCE HEAVY SEDATION; THEREFORE, EQUIPMENT
NECESSARY TO MAINTAIN A PATENT AIRWAY AND TO SUPPORT
RESPIRATION/VENTILATION SHOULD BE AVAILABLE.
As is true of similar CNS-acting drugs, the decision as to when patients who have
received injectable lorazepam, particularly on an outpatient basis, may again operate
machinery, drive a motor vehicle, or engage in hazardous or other activities requiring
attention and coordination must be individualized. It is recommended that no patient
engage in such activities for a period of 24 to 48 hours or until the effects of the drug,
such as drowsiness, have subsided, whichever is longer. Impairment of performance may
persist for greater intervals because of extremes of age, concomitant use of other drugs,
stress of surgery, or the general condition of the patient.
Clinical trials have shown that patients over the age of 50 years may have a more
profound and prolonged sedation with intravenous lorazepam (see also DOSAGE AND
ADMINISTRATION, Preanesthetic).
As with all central-nervous-system-depressant drugs, care should be exercised in patients
given injectable lorazepam as premature ambulation may result in injury from falling.
There is no added beneficial effect from the addition of scopolamine to injectable
lorazepam, and their combined effect may result in an increased incidence of sedation,
hallucination and irrational behavior.
General (All Uses)
PRIOR TO INTRAVENOUS USE, ATIVAN INJECTION MUST BE DILUTED WITH
AN EQUAL AMOUNT OF COMPATIBLE DILUENT (see DOSAGE AND
ADMINISTRATION). INTRAVENOUS INJECTION SHOULD BE MADE SLOWLY
AND WITH REPEATED ASPIRATION. CARE SHOULD BE TAKEN TO
DETERMINE THAT ANY INJECTION WILL NOT BE INTRA-ARTERIAL AND
THAT PERIVASCULAR EXTRAVASATION WILL NOT TAKE PLACE. IN THE
EVENT THAT A PATIENT COMPLAINS OF PAIN DURING INTENDED
INTRAVENOUS INJECTION OF ATIVAN INJECTION, THE INJECTION SHOULD
BE STOPPED IMMEDIATELY TO DETERMINE IF INTRA-ARTERIAL INJECTION
OR PERIVASCULAR EXTRAVASATION HAS TAKEN PLACE.
Since the liver is the most likely site of conjugation of lorazepam and since excretion of
conjugated lorazepam (glucuronide) is a renal function, this drug is not recommended for
use in patients with hepatic and/or renal failure. ATIVAN should be used with caution in
patients with mild-to-moderate hepatic or renal disease (see DOSAGE AND
ADMINISTRATION).
Pregnancy
ATIVAN MAY CAUSE FETAL DAMAGE WHEN ADMINISTERED TO
PREGNANT WOMEN. Ordinarily, ATIVAN Injection should not be used during
pregnancy except in serious or life-threatening conditions where safer drugs
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8
cannot be used or are ineffective. Status epilepticus may represent such a serious
and life-threatening condition.
An increased risk of congenital malformations associated with the use of minor
tranquilizers (chlordiazepoxide, diazepam and meprobamate) during the first trimester of
pregnancy has been suggested in several studies. In humans, blood levels obtained from
umbilical cord blood indicate placental transfer of lorazepam and lorazepam glucuronide.
Reproductive studies in animals were performed in mice, rats, and two strains of rabbits.
Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated limbs,
gastroschisis, malformed skull, and microphthalmia) were seen in drug-treated rabbits
without relationship to dosage. Although all of these anomalies were not present in the
concurrent control group, they have been reported to occur randomly in historical
controls. At doses of 40 mg/kg orally or 4 mg/kg intravenously and higher, there was
evidence of fetal resorption and increased fetal loss in rabbits which was not seen at
lower doses.
The possibility that a woman of childbearing potential may be pregnant at the time of
therapy should be considered.
There are insufficient data regarding obstetrical safety of parenteral lorazepam, including
use in cesarean section. Such use, therefore, is not recommended.
Endoscopic Procedures
There are insufficient data to support the use of ATIVAN Injection for outpatient
endoscopic procedures. Inpatient endoscopic procedures require adequate recovery room
observation time.
When ATIVAN Injection is used for peroral endoscopic procedures; adequate topical
or regional anesthesia is recommended to minimize reflex activity associated with
such procedures.
PRECAUTIONS
General
The additive central-nervous-system effects of other drugs, such as phenothiazines,
narcotic analgesics, barbiturates, antidepressants, scopolamine, and monoamine-oxidase
inhibitors, should be borne in mind when these other drugs are used concomitantly with
or during the period of recovery from ATIVAN Injection (see CLINICAL
PHARMACOLOGY and WARNINGS).
Extreme caution must be used when administering ATIVAN Injection to elderly patients,
very ill patients, or to patients with limited pulmonary reserve because of the possibility
that hypoventilation and/or hypoxic cardiac arrest may occur. Resuscitative equipment
for ventilatory support should be readily available (see WARNINGS and DOSAGE
AND ADMINISTRATION).
When lorazepam injection is used IV as the premedicant prior to regional or local
anesthesia, the possibility of excessive sleepiness or drowsiness may interfere with
patient cooperation in determining levels of anesthesia. This is most likely to occur when
greater than 0.05 mg/kg is given and when narcotic analgesics are used concomitantly
with the recommended dose (see ADVERSE REACTIONS).
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9
As with all benzodiazepines, paradoxical reactions may occur in rare instances and in an
unpredictable fashion (see ADVERSE REACTIONS). In these instances, further use of
the drug in these patients should be considered with caution.
There have been reports of possible propylene glycol toxicity (e.g., lactic acidosis,
hyperosmolality, hypotension) and possible polyethylene glycol toxicity (e.g.,
acute tubular necrosis) during administration of ATIVAN Injection at higher than
recommended doses. Symptoms may be more likely to develop in patients with
renal impairment.
Information for Patients
Patients should be informed of the pharmacological effects of the drug, including
sedation, relief of anxiety, and lack of recall, the duration of these effects (about 8 hours),
and be apprised of the risks as well as the benefits of therapy.
Patients who receive ATIVAN Injection as a premedicant should be cautioned that
driving a motor vehicle, operating machinery, or engaging in hazardous or other activities
requiring attention and coordination, should be delayed for 24 to 48 hours following the
injection or until the effects of the drug, such as drowsiness, have subsided, whichever is
longer. Sedatives, tranquilizers and narcotic analgesics may produce a more prolonged
and profound effect when administered along with injectable ATIVAN. This effect may
take the form of excessive sleepiness or drowsiness and, on rare occasions, interfere with
recall and recognition of events of the day of surgery and the day after.
Patients should be advised that getting out of bed unassisted may result in falling and
injury if undertaken within 8 hours of receiving lorazepam injection. Since tolerance for
CNS depressants will be diminished in the presence of ATIVAN Injection, these
substances should either be avoided or taken in reduced dosage. Alcoholic beverages
should not be consumed for at least 24 to 48 hours after receiving lorazepam injectable
due to the additive effects on central-nervous-system depression seen with
benzodiazepines in general. Elderly patients should be told that ATIVAN Injection may
make them very sleepy for a period longer than 6 to 8 hours following surgery.
Laboratory Tests
In clinical trials, no laboratory test abnormalities were identified with either single or
multiple doses of ATIVAN Injection. These tests included: CBC, urinalysis, SGOT,
SGPT, bilirubin, alkaline phosphatase, LDH, cholesterol, uric acid, BUN, glucose,
calcium, phosphorus, and total proteins.
Drug Interactions
ATIVAN Injection, like other injectable benzodiazepines, produces additive depression
of the central nervous system when administered with other CNS depressants such as
ethyl alcohol, phenothiazines, barbiturates, MAO inhibitors, and other antidepressants.
When scopolamine is used concomitantly with injectable lorazepam, an increased
incidence of sedation, hallucinations and irrational behavior has been observed.
There have been rare reports of significant respiratory depression, stupor and/or
hypotension with the concomitant use of loxapine and lorazepam.
Marked sedation, excessive salivation, ataxia, and, rarely, death have been reported with
the concomitant use of clozapine and lorazepam.
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10
Apnea, coma, bradycardia, arrhythmia, heart arrest, and death have been reported with
the concomitant use of haloperidol and lorazepam.
The risk of using lorazepam in combination with scopolamine, loxapine, clozapine,
haloperidol, or other CNS-depressant drugs has not been systematically evaluated.
Therefore, caution is advised if the concomitant administration of lorazepam and these
drugs is required.
Concurrent administration of any of the following drugs with lorazepam had no effect on
the pharmacokinetics of lorazepam: metoprolol, cimetidine, ranitidine, disulfiram,
propranolol, metronidazole, and propoxyphene. No change in ATIVAN dosage is
necessary when concomitantly given with any of these drugs.
Lorazepam-Valproate Interaction
Concurrent administration of lorazepam (2 mg intravenously) with valproate (250 mg
twice daily orally for 3 days) to 6 healthy male subjects resulted in decreased total
clearance of lorazepam by 40% and decreased formation rate of lorazepam glucuronide
by 55%, as compared with lorazepam administered alone. Accordingly, lorazepam
plasma concentrations were about two-fold higher for at least 12 hours post-dose
administration during valproate treatment. Lorazepam dosage should be reduced to 50%
of the normal adult dose when this drug combination is prescribed in patients (see also
DOSAGE AND ADMINISTRATION).
Lorazepam-Oral Contraceptive Steroids Interaction
Coadministration of lorazepam (2 mg intravenously) with oral contraceptive steroids
(norethindrone acetate, 1 mg, and ethinyl estradiol, 50 μg, for at least 6 months) to
healthy females (n=7) was associated with a 55% decrease in half-life, a 50% increase in
the volume of distribution, thereby resulting in an almost 3.7-fold increase in total
clearance of lorazepam as compared with control healthy females (n=8). It may be
necessary to increase the dose of ATIVAN in female patients who are concomitantly
taking oral contraceptives (see also DOSAGE AND ADMINISTRATION).
Lorazepam-Probenecid Interaction
Concurrent administration of lorazepam (2 mg intravenously) with probenecid (500 mg
orally every 6 hours) to 9 healthy volunteers resulted in a prolongation of lorazepam
half-life by 130% and a decrease in its total clearance by 45%. No change in volume of
distribution was noted during probenecid co-treatment. ATIVAN dosage needs to be
reduced by 50% when coadministered with probenecid (see also DOSAGE AND
ADMINISTRATION).
Drug/Laboratory Test Interactions
No laboratory test abnormalities were identified when lorazepam was given alone or
concomitantly with another drug, such as narcotic analgesics, inhalation anesthetics,
scopolamine, atropine, and a variety of tranquilizing agents.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential emerged in rats and mice during an 18-month
study with oral lorazepam. No studies regarding mutagenesis have been performed. The
results of a preimplantation study in rats, in which the oral lorazepam dose was 20 mg/kg,
showed no impairment of fertility.
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11
Pregnancy
Teratogenic Effects—Pregnancy Category D (See WARNINGS.)
Labor and Delivery
There are insufficient data to support the use of ATIVAN (lorazepam) Injection during
labor and delivery, including cesarean section; therefore, its use in this clinical
circumstance is not recommended.
Nursing Mothers
Lorazepam has been detected in human breast milk. Therefore, lorazepam should not be
administered to nursing mothers because, like other benzodiazepines, the possibility
exists that lorazepam may sedate or otherwise adversely affect the infant.
Pediatric Use
Status Epilepticus
The safety of ATIVAN in pediatric patients with status epilepticus has not been
systematically evaluated. Open-label studies described in the medical literature included
273 pediatric/adolescent patients; the age range was from a few hours old to 18 years of
age. Paradoxical excitation was observed in 10% to 30% of the pediatric patients under 8
years of age and was characterized by tremors, agitation, euphoria, logorrhea, and brief
episodes of visual hallucinations. Paradoxical excitation in pediatric patients also has
been reported with other benzodiazepines when used for status epilepticus, as an
anesthesia, or for pre-chemotherapy treatment.
Pediatric patients (as well as adults) with atypical petit mal status epilepticus have
developed brief tonic-clonic seizures shortly after ATIVAN was given. This
“paradoxical” effect was also reported for diazepam and clonazepam. Nevertheless, the
development of seizures after treatment with benzodiazepines is probably rare, based on
the incidence in the uncontrolled treatment series reported (i.e., seizures were not
observed for 112 pediatric patients and 18 adults or during approximately 400 doses).
Preanesthetic
There are insufficient data to support the efficacy of injectable lorazepam as a
preanesthetic agent in patients less than 18 years of age.
General
Seizure activity and myoclonus have been reported to occur following administration of
ATIVAN Injection, especially in very low birth weight neonates.
Pediatric patients may exhibit a sensitivity to benzyl alcohol, polyethylene glycol and
propylene glycol, components of ATIVAN Injection (see also
CONTRAINDICATIONS). The “gasping syndrome”, characterized by central nervous
system depression, metabolic acidosis, gasping respirations, and high levels of benzyl
alcohol and its metabolites found in the blood and urine, has been associated with the
administration of intravenous solutions containing the preservative benzyl alcohol in
neonates. Additional symptoms may include gradual neurological deterioration, seizures,
intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal
failure, hypotension, bradycardia, and cardiovascular collapse. Central nervous system
toxicity, including seizures and intraventricular hemorrhage, as well as unresponsiveness,
tachypnea, tachycardia, and diaphoresis have been associated with propylene glycol
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12
toxicity. Although normal therapeutic doses of ATIVAN Injection contain very small
amounts of these compounds, premature and low-birth-weight infants as well as pediatric
patients receiving high doses may be more susceptible to their effects.
Geriatric Use
Clinical studies of ATIVAN generally were not adequate to determine whether subjects
aged 65 and over respond differently than younger subjects; however, age over 65 may
be associated with a greater incidence of central nervous system depression and more
respiratory depression (see WARNINGS–Preanesthetic Use, PRECAUTIONS–
General and ADVERSE REACTIONS–Preanesthetic).
Age does not appear to have a clinically significant effect on lorazepam kinetics (see
CLINICAL PHARMACOLOGY).
Clinical circumstances, some of which may be more common in the elderly, such as
hepatic or renal impairment, should be considered. Greater sensitivity (e.g., sedation) of
some older individuals cannot be ruled out. In general, dose selection for an elderly
patient should be cautious, usually starting at the low end of the dosing range (see
DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Status Epilepticus
The most important adverse clinical event caused by the use of ATIVAN Injection is
respiratory depression (see WARNINGS).
The adverse clinical events most commonly observed with the use of ATIVAN Injection
in clinical trials evaluating its use in status epilepticus were hypotension, somnolence,
and respiratory failure.
Incidence in Controlled Clinical Trials
All adverse events were recorded during the trials by the clinical investigators using
terminology of their own choosing. Similar types of events were grouped into
standardized categories using modified COSTART dictionary terminology. These
categories are used in the table and listings below with the frequencies representing the
proportion of individuals exposed to ATIVAN Injection or to comparative therapy.
The prescriber should be aware that these figures cannot be used to predict the frequency
of adverse events in the course of usual medical practice where patient characteristics and
other factors may differ from those prevailing during clinical studies. Similarly, the cited
frequencies cannot be directly compared with figures obtained from other clinical
investigators involving different treatment, uses, or investigators. An inspection of these
frequencies, however, does provide the prescribing physician with one basis to estimate
the relative contribution of drug and nondrug factors to the adverse event incidences in
the population studied.
Commonly Observed Adverse Events in a Controlled Dose-Comparison Clinical
Trial
Table 1 lists the treatment-emergent adverse events that occurred in the patients treated
with ATIVAN Injection in a dose-comparison trial of ATIVAN 1 mg, 2 mg, and 4 mg.
TABLE 1. NUMBER (%) OF STUDY EVENTS IN A
DOSE COMPARISON CLINICAL TRIAL
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Body System
Event
ATIVAN Injection
(n=130)a
Any Study Event (1 or more)b
16 (12.3%)
Body as a whole
Infection
1 ( <1%)
Cardiovascular system
Hypotension
2 (1.5%)
Digestive system
Liver function tests abnormal
Nausea
Vomiting
1 ( <1%)
1 ( <1%)
1 ( <1%)
Metabolic and Nutritional
Acidosis
1 ( <1%)
Nervous system
Brain edema
Coma
Convulsion
Somnolence
Thinking abnormal
1 ( <1%)
1 ( <1%)
1 ( <1%)
2 (1.5%)
1 ( <1%)
Respiratory system
Hyperventilation
Hypoventilation
Respiratory failure
1 ( <1%)
1 ( <1%)
2 (1.5%)
Terms not classifiable
Injection site reaction
1 ( <1%)
Urogenital system
Cystitis
1 ( <1%)
a: One hundred and thirty (130) patients received ATIVAN Injection.
b: Totals are not necessarily the sum of the individual study events because a patient may
report two or more different study events in the same body system.
Commonly Observed Adverse Events in Active-Controlled Clinical Trials
In two studies, patients who completed the course of treatment for status epilepticus were
permitted to be reenrolled and to receive treatment for a second status episode, given that
there was a sufficient interval between the two episodes. Safety was determined from all
treatment episodes for all intent-to-treat patients, i.e., from all “patient-episodes.” Table 2
lists the treatment-emergent adverse events that occurred in at least 1% of the patient-
episodes in which ATIVAN Injection or diazepam was given. The table represents the
pooling of results from the two controlled trials.
TABLE 2. NUMBER (%) OF STUDY EVENTS IN ACTIVE CONTROLLED
CLINICAL TRIAL
Body System
Event
ATIVAN Injection
(n=85)a
Diazepam
(n=80)a
Any Study Event (1 or more)b
14 (16.5%)
11 (13.8%)
Body as a whole
Headache
1 ( 1.2%)
1 (1.3%)
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14
Cardiovascular system
Hypotension
2 (2.4%)
0
Hemic and lymphatic system
Hypochromic anemia
Leukocytosis
Thrombocythemia
0
0
0
1 (1.3%)
1 (1.3%)
1 (1.3%)
Nervous system
Coma
Somnolence
Stupor
1 (1.2 %)
3 (3.5%)
1 (1.2%)
1 (1.3%)
3 (3.8%)
0
Respiratory system
Hypoventilation
Apnea
Respiratory failure
Respiratory disorder
1 (1.2%)
1 (1.2%)
2 (2.4%)
1 (1.2%)
2 (2.5%)
1 (1.3%)
1 (1.3%)
0
a: The number indicates the number of “patient-episodes.” Patient-episodes were used
rather than “patients” because a total of 7 patients were reenrolled for the treatment of a
second episode of status: 5 patients received ATIVAN Injection on two occasions that
were far enough apart to establish the diagnosis of status epilepticus for each episode,
and, using the same time criterion, 2 patients received diazepam on two occasions.
b: Totals are not necessarily the sum of the individual study events because a patient may
report two or more different study events in the same body system.
These trials were not designed or intended to demonstrate the comparative safety of the
two treatments.
The overall adverse experience profile for ATIVAN was similar between women and
men. There are insufficient data to support a statement regarding the distribution of
adverse events by race. Generally, age greater than 65 years may be associated with a
greater incidence of central-nervous-system depression and more respiratory depression.
Other Events Observed During the Pre-Marketing Evaluation of Ativan Injection
for the Treatment of Status Epilepticus
ATIVAN Injection, active comparators, and ATIVAN Injection in combination with a
comparator were administered to 488 individuals during controlled and open-label
clinical trials. Because of reenrollments, these 488 patients participated in a total of 521
patient-episodes. ATIVAN Injection alone was given in 69% of these patient-episodes
(n=360). The safety information below is based on data available from 326 of these
patient-episodes in which ATIVAN Injection was given alone.
All adverse events that were seen once are listed, except those already included in
previous listings (Table 1 and Table 2).
Study events were classified by body system in descending frequency by using the
following definitions: frequent adverse events were those that occurred in at least 1/100
individuals; infrequent study events were those that occurred in 1/100 to 1/1000
individuals.
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Frequent and Infrequent Study Events
Body as a Whole -
Infrequent: asthenia, chills, headache,
infection.
Digestive System -
Infrequent: abnormal liver function test,
increased salivation, nausea, vomiting.
Metabolic and Nutritional -
Infrequent: acidosis, alkaline phosphatase
increased.
Nervous System -
Infrequent: agitation, ataxia, brain edema,
coma, confusion, convulsion, hallucinations,
myoclonus, stupor, thinking abnormal, tremor.
Respiratory System -
Frequent: apnea; Infrequent: hyperventilation,
hypoventilation, respiratory disorder.
Terms Not Classifiable -
Infrequent: injection site reaction.
Urogenital System -
Infrequent: cystitis.
Preanesthetic
Central Nervous System
The most frequent adverse drug event reported with injectable lorazepam is central-
nervous-system depression. The incidence varied from one study to another, depending
on the dosage, route of administration, use of other central-nervous-system depressants,
and the investigator’s opinion concerning the degree and duration of desired sedation.
Excessive sleepiness and drowsiness were the most common consequences of CNS
depression. This interfered with patient cooperation in approximately 6% (25/446) of
patients undergoing regional anesthesia, causing difficulty in assessing levels of
anesthesia. Patients over 50 years of age had a higher incidence of excessive sleepiness
or drowsiness when compared with those under 50 (21/106 versus 24/245) when
lorazepam was given intravenously (see DOSAGE AND ADMINISTRATION). On
rare occasion (3/1580) the patient was unable to give personal identification in the
operating room on arrival, and one patient fell when attempting premature ambulation in
the postoperative period.
Symptoms such as restlessness, confusion, depression, crying, sobbing, and delirium
occurred in about 1.3% (20/1580). One patient injured himself by picking at his incision
during the immediate postoperative period.
Hallucinations were present in about 1% (14/1580) of patients and were visual and
self-limiting.
An occasional patient complained of dizziness, diplopia and/or blurred vision. Depressed
hearing was infrequently reported during the peak-effect period.
An occasional patient had a prolonged recovery room stay, either because of excessive
sleepiness or because of some form of inappropriate behavior. The latter was seen most
commonly when scopolamine was given concomitantly as a premedicant. Limited
information derived from patients who were discharged the day after receiving injectable
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lorazepam showed one patient complained of some unsteadiness of gait and a reduced
ability to perform complex mental functions. Enhanced sensitivity to alcoholic beverages
has been reported more than 24 hours after receiving injectable lorazepam, similar to
experience with other benzodiazepines.
Local Effects
Intramuscular injection of lorazepam has resulted in pain at the injection site, a sensation
of burning, or observed redness in the same area in a very variable incidence from one
study to another. The overall incidence of pain and burning in patients was about 17%
(146/859) in the immediate postinjection period and about 1.4% (12/859) at the 24-hour
observation time. Reactions at the injection site (redness) occurred in approximately 2%
(17/859) in the immediate postinjection period and were present 24 hours later in about
0.8% (7/859).
Intravenous administration of lorazepam resulted in painful responses in 13/771 patients
or approximately 1.6% in the immediate postinjection period, and 24 hours later 4/771
patients or about 0.5% still complained of pain. Redness did not occur immediately
following intravenous injection but was noted in 19/771 patients at the 24-hour
observation period. This incidence is similar to that observed with an intravenous
infusion before lorazepam is given. Intra-arterial injection may produce arteriospasm
resulting in gangrene which may require amputation (see CONTRAINDICATIONS).
Cardiovascular System
Hypertension (0.1%) and hypotension (0.1%) have occasionally been observed after
patients have received injectable lorazepam.
Respiratory System
Five patients (5/446) who underwent regional anesthesia were observed to have airway
obstruction. This was believed due to excessive sleepiness at the time of the procedure
and resulted in temporary hypoventilation. In this instance, appropriate airway
management may become necessary (see also CLINICAL PHARMACOLOGY,
WARNINGS and PRECAUTIONS).
Other Adverse Experiences
Skin rash, nausea and vomiting have occasionally been noted in patients who have
received injectable lorazepam combined with other drugs during anesthesia and surgery.
Paradoxical Reactions
As with all benzodiazepines, paradoxical reactions such as stimulation, mania,
irritability, restlessness, agitation, aggression, psychosis, hostility, rage, or
hallucinations may occur in rare instances and in an unpredictable fashion. In these
instances, further use of the drug in these patients should be considered with caution
(see PRECAUTIONS, General).
Postmarketing Reports
Voluntary reports of other adverse events temporally associated with the use of ATIVAN
(lorazepam) Injection that have been received since market introduction and that may
have no causal relationship with the use of ATIVAN Injection include the following:
acute brain syndrome, aggravation of pheochromocytoma, amnesia, apnea/respiratory
arrest, arrhythmia, bradycardia, brain edema, coagulation disorder, coma, convulsion,
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gastrointestinal hemorrhage, heart arrest/failure, heart block, liver damage, lung edema,
lung hemorrhage, nervousness, neuroleptic malignant syndrome, paralysis, pericardial
effusion, pneumothorax, pulmonary hypertension, tachycardia, thrombocytopenia,
urinary incontinence, ventricular arrhythmia.
Fatalities also have been reported, usually in patients on concomitant medications
(e.g., respiratory depressants) and/or with other medical conditions (e.g., obstructive
sleep apnea).
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Lorazepam is a controlled substance in Schedule IV.
Abuse and Physical and Psychological Dependence
As with other benzodiazepines, ATIVAN Injection has a potential for abuse and may
lead to dependence. Physicians should be aware that repeated doses over a prolonged
period of time may result in physical and psychological dependence and withdrawal
symptoms, following abrupt discontinuance, similar in character to those noted with
barbiturates and alcohol.
OVERDOSAGE
Symptoms
Overdosage of benzodiazepines is usually manifested by varying degrees of central-
nervous-system depression, ranging from drowsiness to coma. In mild cases symptoms
include drowsiness, mental confusion and lethargy. In more serious examples, symptoms
may include ataxia, hypotonia, hypotension, hypnosis, stages one (1) to three (3) coma,
and, very rarely, death.
Treatment
Treatment of overdosage is mainly supportive until the drug is eliminated from the body.
Vital signs and fluid balance should be carefully monitored in conjunction with close
observation of the patient. An adequate airway should be maintained and assisted
respiration used as needed. With normally functioning kidneys, forced diuresis with
intravenous fluids and electrolytes may accelerate elimination of benzodiazepines from
the body. In addition, osmotic diuretics, such as mannitol, may be effective as adjunctive
measures. In more critical situations, renal dialysis and exchange blood transfusions may
be indicated. Lorazepam does not appear to be removed in significant quantities by
dialysis, although lorazepam glucuronide may be highly dialyzable. The value of dialysis
has not been adequately determined for lorazepam.
The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an
adjunct to, not as a substitute for, proper management of benzodiazepine overdose. The
prescriber should be aware of a risk of seizure in association with flumazenil
treatment, particularly in long-term benzodiazepine users and in cyclic
antidepressant overdose. The complete flumazenil package insert including
CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted
prior to use.
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DOSAGE AND ADMINISTRATION
ATIVAN must never be used without individualization of dosage particularly when used
with other medications capable of producing central-nervous-system depression.
EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY SHOULD BE
IMMEDIATELY AVAILABLE PRIOR TO INTRAVENOUS ADMINISTRATION OF
LORAZEPAM (see WARNINGS).
Status Epilepticus
General Advice
Status epilepticus is a potentially life-threatening condition associated with a high risk of
permanent neurological impairment, if inadequately treated. The treatment of status,
however, requires far more than the administration of an anticonvulsant agent. It involves
observation and management of all parameters critical to maintaining vital function and
the capacity to provide support of those functions as required. Ventilatory support must
be readily available. The use of benzodiazepines, like ATIVAN Injection, is ordinarily
only an initial step of a complex and sustained intervention which may require additional
interventions, (e.g., concomitant intravenous administration of phenytoin). Because status
epilepticus may result from a correctable acute cause such as hypoglycemia,
hyponatremia, or other metabolic or toxic derangement, such an abnormality must be
immediately sought and corrected. Furthermore, patients who are susceptible to further
seizure episodes should receive adequate maintenance antiepileptic therapy.
Any health care professional who intends to treat a patient with status epilepticus should
be familiar with this package insert and the pertinent medical literature concerning
current concepts for the treatment of status epilepticus. A comprehensive review of the
considerations critical to the informed and prudent management of status epilepticus
cannot be provided in drug product labeling. The archival medical literature contains
many informative references on the management of status epilepticus, among them the
report of the working group on status epilepticus of the Epilepsy Foundation of America
“Treatment of Convulsive Status Epilepticus” (JAMA 1993; 270:854-859). As noted in
the report just cited, it may be useful to consult with a neurologist if a patient fails to
respond (e.g., fails to regain consciousness).
Intravenous Injection
For the treatment of status epilepticus, the usual recommended dose of ATIVAN
Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures
cease, no additional ATIVAN Injection is required. If seizures continue or recur after a
10- to 15-minute observation period, an additional 4 mg intravenous dose may be slowly
administered. Experience with further doses of ATIVAN is very limited. The usual
precautions in treating status epilepticus should be employed. An intravenous infusion
should be started, vital signs should be monitored, an unobstructed airway should be
maintained, and artificial ventilation equipment should be available.
Intramuscular Injection
IM ATIVAN is not preferred in the treatment of status epilepticus because therapeutic
lorazepam levels may not be reached as quickly as with IV administration. However,
when an intravenous port is not available, the IM route may prove useful (see
CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).
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19
Pediatric
The safety of ATIVAN in pediatric patients has not been established.
Preanesthetic
Intramuscular Injection
For the designated indications as a premedicant, the usual recommended dose of
lorazepam for intramuscular injection is 0.05 mg/kg up to a maximum of 4 mg. As with
all premedicant drugs, the dose should be individualized (see also CLINICAL
PHARMACOLOGY, WARNINGS, PRECAUTIONS, and ADVERSE
REACTIONS). Doses of other central-nervous-system-depressant drugs ordinarily
should be reduced (see PRECAUTIONS). For optimum effect, measured as lack of
recall, intramuscular lorazepam should be administered at least 2 hours before the
anticipated operative procedure. Narcotic analgesics should be administered at their
usual preoperative time.
There are insufficient data to support efficacy or make dosage recommendations for
intramuscular lorazepam in patients less than 18 years of age; therefore, such use is
not recommended.
Intravenous Injection
For the primary purpose of sedation and relief of anxiety, the usual recommended initial
dose of lorazepam for intravenous injection is 2 mg total, or 0.02 mg/lb (0.044 mg/kg),
whichever is smaller. This dose will suffice for sedating most adult patients and
ordinarily should not be exceeded in patients over 50 years of age. In those patients in
whom a greater likelihood of lack of recall for perioperative events would be beneficial,
larger doses as high as 0.05 mg/kg up to a total of 4 mg may be administered (see
CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS, and ADVERSE
REACTIONS). Doses of other injectable central-nervous-system-depressant drugs
ordinarily should be reduced (see PRECAUTIONS). For optimum effect, measured as
lack of recall, intravenous lorazepam should be administered 15 to 20 minutes before the
anticipated operative procedure.
There are insufficient data to support efficacy or make dosage recommendations for
intravenous lorazepam in patients less than 18 years of age; therefore, such use is
not recommended.
Dose Administration in Special Populations
Elderly Patients and Patients With Hepatic Disease
No dosage adjustments are needed in elderly patients and in patients with hepatic disease.
Patients With Renal Disease
For acute dose administration, adjustment is not needed for patients with renal disease.
However, in patients with renal disease, caution should be exercised if frequent doses are
given over relatively short periods of time (see also CLINICAL PHARMACOLOGY).
Dose Adjustment Due to Drug Interactions
The dose of ATIVAN should be reduced by 50% when coadministered with probenecid
or valproate (see PRECAUTIONS, Drug Interactions).
It may be necessary to increase the dose of ATIVAN in female patients who are
concomitantly taking oral contraceptives.
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20
Administration
When given intramuscularly, ATIVAN Injection, undiluted, should be injected deep in
the muscle mass.
Injectable ATIVAN can be used with atropine sulfate, narcotic analgesics, other
parenterally used analgesics, commonly used anesthetics, and muscle relaxants.
Immediately prior to intravenous use, ATIVAN Injection must be diluted with an equal
volume of compatible solution. Contents should be mixed thoroughly by gently inverting
the container repeatedly until a homogenous solution results. Do not shake vigorously, as
this will result in air entrapment. When properly diluted, the drug may be injected
directly into a vein or into the tubing of an existing intravenous infusion. The rate of
injection should not exceed 2.0 mg per minute.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit. Do not use
if solution is discolored or contains a precipitate.
ATIVAN Injection is compatible for dilution purposes with the following solutions:
Sterile Water for Injection, USP; Sodium Chloride Injection, USP; 5% Dextrose
Injection, USP.
HOW SUPPLIED
ATIVAN (lorazepam) Injection is available in the following dosage strengths in
single-dose and multiple-dose vials:
2 mg per mL, NDC 60977-112-01, 25 x 1 mL vial
NDC 60977-112-02, 10 x 10 mL vial
4 mg per mL, NDC 60977-113-01, 25 x 1 mL vial
NDC 60977-113-02, 10 x 10 mL vial
For IM or IV injection.
Store in a refrigerator.
PROTECT FROM LIGHT.
Use carton to protect contents from light.
ATIVAN is a trademark of Biovail Laboratories, Ltd.
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
MLT-01086/1.0
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|
custom-source
|
2025-02-12T13:44:37.449484
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018140s028lbl.pdf', 'application_number': 18140, 'submission_type': 'SUPPL ', 'submission_number': 28}
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11,170
|
FELDENE®
(piroxicam)
CAPSULES
10 mg and 20 mg
For Oral Use
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with
cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
• FELDENE is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur
at any time during use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
DESCRIPTION
FELDENE® contains piroxicam which is a member of the oxicam group of nonsteroidal
anti-inflammatory drugs (NSAIDs). Each maroon and blue capsule contains 10 mg piroxicam, each
maroon capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is
4-hydroxyl-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. Piroxicam
occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It
is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton
(pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). The molecular weight of piroxicam is 331.35.
Its molecular formula is C15H13N3O4S and it has the following structural formula:
O
C
NH
OH
N
CH3
S
O2
N
5
6
7
8
1
2
3
4
2′
6′
5′
4′
3′
Reference ID: 3708816
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The inactive ingredients in FELDENE capsules include: Blue 1, Red 3, lactose, magnesium stearate,
sodium lauryl sulfate, starch.
CLINICAL PHARMACOLOGY
Pharmacodynamics
FELDENE is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory,
analgesic, and antipyretic activities in animal models. The mechanism of action of FELDENE, like that
of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase
inhibition.
Pharmacokinetics
Absorption: FELDENE is well absorbed following oral administration. Drug plasma concentrations
are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication.
The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations
throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single
20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum
drug plasma concentrations, after repeated daily ingestion of 20 mg FELDENE, usually stabilize at 3–
8 mcg/mL. Most patients approximate steady state plasma levels within 7–12 days. Higher levels,
which approximate steady state at two to three weeks, have been observed in patients in whom longer
plasma half-lives of piroxicam occurred.
With food there is a slight delay in the rate but not the extent of absorption following oral
administration. The concomitant administration of antacids (aluminum hydroxide or aluminum
hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of
orally administered piroxicam.
Distribution: The apparent volume of distribution of piroxicam is approximately 0.14 L/kg.
Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into
human milk. The presence in breast milk has been determined during initial and long-term conditions
(52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No
accumulation of piroxicam occurred in milk relative to that in plasma during treatment.
Metabolism: Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side
chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving
hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro
studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the
5′-hydroxy-piroxicam, the major metabolite (see Pharmacogenetics, and Special Populations, Poor
Metabolizers of CYP2C9 Substrates). The biotransformation products of piroxicam metabolism are
reported to not have any anti-inflammatory activity.
Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms
compared to normal metabolizer type subjects (see Pharmacogenetics, and Special Populations, Poor
Metabolizers of CYP2C9 Substrates).
Excretion: FELDENE and its biotransformation products are excreted in urine and feces, with about
twice as much appearing in the urine as in the feces. Approximately 5% of a FELDENE dose is
excreted unchanged. The plasma half-life (T½) for piroxicam is approximately 50 hours.
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Pharmacogenetics: CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as
the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that
subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous
CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels,
respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following
administration of an oral single dose. The mean elimination half life values of piroxicam for subjects
with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than
subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3
genotype is 0% to 1% in the population at large; however, frequencies as high as 5.7% have been
reported in certain ethnic groups.
Special Populations
Pediatric: FELDENE has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been identified.
Hepatic Insufficiency: The effects of hepatic disease on FELDENE pharmacokinetics have not been
established. However, a substantial portion of FELDENE elimination occurs by hepatic metabolism.
Consequently, patients with hepatic disease may require reduced doses of FELDENE as compared to
patients with normal hepatic function.
Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9
metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as
warfarin and phenytoin) should be administered piroxicam with caution as they may have abnormally
high plasma levels due to reduced metabolic clearance.
Renal Insufficiency: FELDENE pharmacokinetics have been investigated in patients with renal
insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing
adjustments. However, the pharmacokinetic properties of FELDENE in patients with severe renal
insufficiency or those receiving hemodialysis are not known.
Other Information
In controlled clinical trials, the effectiveness of FELDENE has been established for both acute
exacerbations and long-term management of rheumatoid arthritis and osteoarthritis.
The therapeutic effects of FELDENE are evident early in the treatment of both diseases with a
progressive increase in response over several (8–12) weeks. Efficacy is seen in terms of pain relief and,
when present, subsidence of inflammation.
Doses of 20 mg/day FELDENE display a therapeutic effect comparable to therapeutic doses of aspirin,
with a lower incidence of minor gastrointestinal effects and tinnitus.
FELDENE has been administered concomitantly with fixed doses of gold and corticosteroids. The
existence of a “steroid-sparing” effect has not been adequately studied to date.
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INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
FELDENE is indicated:
• For relief of the signs and symptoms of osteoarthritis.
• For relief of the signs and symptoms of rheumatoid arthritis.
CONTRAINDICATIONS
FELDENE is contraindicated in patients with known hypersensitivity to piroxicam.
FELDENE should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and
PRECAUTIONS: Preexisting Asthma).
FELDENE is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV
thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of
Ulceration, Bleeding, and Perforation).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
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Hypertension
NSAIDs, including FELDENE, can lead to onset of new hypertension or worsening of preexisting
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including FELDENE, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the
course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. FELDENE should be
used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including FELDENE, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4%
of patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk of GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, or
anticoagulants, longer duration of NSAID therapy; smoking; use of alcohol; older age; and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and, therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients,
alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
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Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of FELDENE in patients
with advanced renal disease. Therefore, treatment with FELDENE is not recommended in these
patients with advanced renal disease. If FELDENE therapy must be initiated, close monitoring of the
patient’s renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to
FELDENE. FELDENE should not be given to patients with the aspirin triad. This symptom complex
typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including FELDENE, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs and symptoms
of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
Other Hypersensitivity Reactions
A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness
have occasionally occurred in conjunction with the use of FELDENE. These include arthralgias,
pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis.
Pregnancy
In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
FELDENE cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of FELDENE in reducing fever and inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs,
including FELDENE. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more
times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials
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with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant
hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of more severe hepatic reaction
while on therapy with FELDENE. If clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), FELDENE should be discontinued
(see ADVERSE REACTIONS).
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including FELDENE. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including FELDENE, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving FELDENE who may be adversely affected by alterations in platelet function, such as
those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Ophthalmologic Effects
Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is
recommended that patients who develop visual complaints during treatment with FELDENE have
ophthalmic evaluations.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with
aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since
cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, FELDENE should not be administered to
patients with this form of aspirin sensitivity and should be used with caution in patients with
preexisting asthma.
Reversible Delayed Ovulation
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including FELDENE,
may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility
in some women. Animal studies have shown that administration of prostaglandin synthesis inhibitors
has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small
studies in women taking NSAIDs have also shown a reversible delay in ovulation. Therefore, in
women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal
of NSAIDs, including FELDENE, should be considered.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
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• FELDENE, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may
result in hospitalization and even death. Although serious CV events can occur without warning
symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any
indicative signs or symptoms. Patients should be apprised of the importance of this follow-up
(see WARNINGS, CARDIOVASCULAR EFFECTS).
• FELDENE, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects,
such as ulcers and bleeding, which may result in hospitalization and even death. Although
serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should
be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia,
melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
• FELDENE, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious
skin reactions may occur without warning, patients should be alert for the signs and symptoms
of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask
for medical advice when observing any indicative signs or symptoms. Patients should be
advised to stop the drug immediately if they develop any type of rash and contact their
physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to
their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical
therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
• In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
• Advise females of reproductive potential who desire pregnancy that NSAIDs, including
Feldene, may be associated with a reversible delay in ovulation For women who have
difficulties conceiving, or who are undergoing investigation of infertility, use of piroxicam is
not recommended (see PRECAUTIONS--Reversible Delayed Ovulation).
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
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consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.), or if abnormal liver tests persist or worsen, FELDENE should be discontinued.
Drug Interactions
Highly Protein Bound Drugs: FELDENE is highly protein bound and, therefore, might be expected to
displace other protein bound drugs. Physicians should closely monitor patients for a change in dosage
requirements when administering FELDENE to patients on other highly protein bound drugs.
Aspirin: When FELDENE is administered with aspirin, its protein binding is reduced, although the
clearance of free FELDENE is not altered. Plasma levels of piroxicam are depressed to approximately
80% of their normal values when FELDENE is administered (20 mg/day) in conjunction with aspirin
(3900 mg/day). The clinical significance of this interaction is not known; however, as with other
NSAIDs, concomitant administration of piroxicam and aspirin is not generally recommended because
of the potential for increased adverse effects.
Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution
should be used when NSAIDs are administered concomitantly with methotrexate.
ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly
with ACE-inhibitors.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Diuretics: Clinical studies, as well as postmarketing observations, have shown that FELDENE can
reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been
attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well
as to assure diuretic efficacy.
Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently,
subjects should be observed carefully for signs of lithium toxicity.
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both
drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Piroxicam has not been adequately evaluated for carcinogenicity.
Piroxicam was not mutagenic in an Ames bacterial reverse mutation assay, or in a dominant lethal
mutation assay in mice, and was not clastogenic in an in vivo chromosome aberration assay in mice.
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Reproductive studies in which rats were administered piroxicam at doses of 2, 5, or 10 mg/kg/day (up
to 5 times the maximum recommended human dose [MRHD] of 20 mg based on mg/m2 body surface
area [BSA]) revealed no impairment of male or female fertility.
Pregnancy
Pregnancy Category C First and Second Trimester
Pregnancy Category D Third Trimester
There are no adequate and well-controlled studies of FELDENE (piroxicam) in pregnant women. Use
of NSAIDs, including FELDENE, during the third trimester of pregnancy increases the risk of
premature closure of the ductus arteriosus. All pregnancies, regardless of drug exposure, have a
background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. During the first and
second trimesters of pregnancy, use FELDENE only if the potential benefit justifies the potential risk
to the fetus. During the third trimester of pregnancy, the patient should be apprised of the potential
hazard to a fetus.
Pregnant rats administered piroxicam 2, 5, or 10 mg/kg/day during the period of organogenesis
(gestation days 6 to 15) demonstrated increased post-implantation losses with 5 and 10 mg/kg/day of
piroxicam (equivalent to 3 and 5 times the maximum recommended human dose [MRHD], of 20 mg
respectively, based on a mg/m2 body surface area [BSA]). There were no drug-related developmental
abnormalities noted in offspring. Gastrointestinal tract toxicity was increased in pregnant rats in the last
trimester of pregnancy compared to non-pregnant rats or rats in earlier trimesters of pregnancy.
Pregnant rabbits administered piroxicam 2, 5, or 10 mg/kg/day during the period of organogenesis
(gestation days 7 to 18) demonstrated no drug-related developmental abnormalities in offspring (up to
11 times the MRHD based on a mg/m2 BSA).
Based on animal data, prostaglandins have shown an important role in endometrial vascular
permeability, blastocyst implantation and decidualization. In animal studies, administration of
prostaglandin synthesis inhibitors such as piroxicam, have been shown to result in increased pre- and
post-implantation loss.
In a pre- and post-natal development study in which pregnant rats were administered piroxicam 2, 5, or
10 mg/kg/day on gestation day 15 through delivery and weaning of offspring, reduced weight gain and
death were observed in dams at 10 mg/kg/day starting gestation day 20 (5 times the MRHD based on a
mg/m2 BSA). Treated dams revealed peritonitis, adhesions, gastric bleeding, hemorrhagic enteritis and
dead fetuses in utero. Parturition was delayed in all piroxicam-treated groups, and there was an
increased incidence of stillbirth. Postnatal development could not be reliably assessed due to the
absence of maternal care secondary to severe maternal toxicity.
Labor and Delivery
The effects of FELDENE on labor or delivery in pregnant women are unknown. In rat studies with
piroxicam, as with other drugs known to inhibit prostaglandin synthesis, delayed parturition and an
increased incidence of stillbirth were noted at doses equivalent to the MRHD of piroxicam.
Nursing Mothers
Piroxicam is present in human milk at about 1% to 3% of the maternal concentration. No accumulation
of piroxicam occurred in milk relative to that in maternal plasma during treatment. The developmental
and health benefits of breastfeeding should be considered along with the mother’s clinical need for
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FELDENE and any potential adverse effects on the breastfed child from the drug or from the
underlying maternal condition. Exercise caution when FELDENE is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
Most spontaneous reports of fatal GI events with NSAIDs are in the elderly or debilitated patients and,
therefore, care should be taken in treating this population. In addition to a past history of ulcer disease,
older age and poor general health status (among other factors) may increase the risk for GI bleeding. To
minimize the potential risk of an adverse GI event, the lowest effective dose should be used for the
shortest possible duration (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,
Bleeding, and Perforation).
As with all other NSAIDs, there is a risk of developing renal toxicity in patients in which renal
prostaglandins have a compensatory role in maintenance of renal perfusion. Discontinuation of
nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state
(see Warnings: Renal Effects).
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting a greater frequency of impaired drug elimination and of concomitant disease or
other drug therapy.
ADVERSE REACTIONS
In patients taking FELDENE or other NSAIDs, the most frequently reported adverse experiences
occurring in approximately 1–10% of patients are:
Cardiovascular System: Edema.
Digestive System: Anorexia, abdominal pain, constipation, diarrhea, dyspepsia, elevated liver
enzymes, flatulence, gross bleeding/perforation, heartburn, nausea, ulcers (gastric/duodenal),
vomiting.
Hemic and Lymphatic System: Anemia, increased bleeding time.
Nervous System: Dizziness, headache.
Skin and Appendages: Pruritus, rash.
Special Senses: Tinnitus.
Urogenital System: Abnormal renal function.
Additional adverse experiences reported occasionally include:
Body As a Whole: Fever, infection, sepsis.
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Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope.
Digestive System: Dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice,
melena, rectal bleeding, stomatitis.
Hemic and Lymphatic System: Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial
rash, thrombocytopenia.
Metabolic and Nutritional: Weight changes, fluid retention.
Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness,
insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo.
Respiratory System: Asthma, dyspnea.
Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat.
Special Senses: Blurred vision.
Urogenital System: Cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic
syndrome, oliguria/polyuria, proteinuria, renal failure, glomerulonephritis.
Other adverse reactions which occur rarely are:
Body As a Whole: Anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic),
serum sickness.
Cardiovascular System: Arrhythmia, exacerbation of angina, hypotension, myocardial infarction,
palpitations, vasculitis.
Digestive System: Eructation, liver failure, pancreatitis.
Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia,
lymphadenopathy, pancytopenia.
Hypersensitivity: Positive ANA.
Metabolic and Nutritional: Hyperglycemia, hypoglycemia.
Nervous System: Akathisia, convulsions, coma, hallucinations, meningitis, mood alterations.
Respiratory: Respiratory depression, pneumonia.
Skin and Appendages: Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative
dermatitis, onycholysis, Stevens-Johnson Syndrome, urticaria, vesiculobullous reaction.
Special Senses: Conjunctivitis, hearing impairment, swollen eyes.
Reproductive system and breast disorders: Female fertility decreased.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea,
vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal
bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but
are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may
occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There
are no specific antidotes. Emesis and/or activated charcoal (60–100 g in adults, 1–2 g/kg in children)
and/or osmotic cathartic may be indicated. The long plasma half-life of piroxicam should be considered
when treating an overdose with piroxicam. Experiments in dogs have demonstrated that the use of
multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam by more than
50% and systemic bioavailability by as much as 37% when activated charcoal is given as late as
6 hours after ingestion of piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or
hemoperfusion may not be useful due to high protein binding.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with FELDENE, the dose and frequency should be
adjusted to suit an individual patient’s needs.
For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is 20 mg given orally
once per day. If desired, the daily dose may be divided. Because of the long half-life of FELDENE,
steady-state blood levels are not reached for 7–12 days. Therefore, although the therapeutic effects of
FELDENE are evident early in treatment, there is a progressive increase in response over several weeks
and the effect of therapy should not be assessed for two weeks.
HOW SUPPLIED
FELDENE® Capsules for oral administration:
Bottles of 100: 10 mg (NDC 0069-3220-66) maroon and blue #322
Bottles of 100: 20 mg (NDC 0069-3230-66) maroon #323
This product’s label may have been updated. For current full prescribing information, please visit
www.pfizer.com.
Store below 86ºF (30ºC)
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LAB-0206-13.3
Revised February 2015
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.
This chance increases:
•
with longer use of NSAID medicines
•
in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft
(CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers
and bleeding:
•
can happen without warning symptoms
•
may cause death
The chance of a person getting an ulcer or bleeding increases with:
•
taking medicines called “corticosteroids” and “anticoagulants”
•
longer use
•
smoking
•
drinking alcohol
•
older age
•
having poor health
NSAID medicines should only be used:
•
exactly as prescribed
•
at the lowest dose possible for your treatment
•
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
•
different types of arthritis
•
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
•
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
•
for pain right before or after heart bypass surgery
Tell your healthcare provider:
•
about all of your medical conditions.
•
about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause
serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
•
if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
•
if you are breastfeeding. Talk to your doctor.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling (fluid retention)
•
kidney problems including kidney failure
•
bleeding and ulcers in the stomach and intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver failure
•
asthma attacks in people who have asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
Get emergency help right away if you have any of the following symptoms:
•
shortness of breath or trouble breathing
•
chest pain
•
weakness in one part or side of your body
•
slurred speech
•
swelling of the face or throat
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:
•
nausea
•
more tired or weaker than usual
•
itching
•
your skin or eyes look yellow
•
stomach pain
•
flu-like symptoms
•
vomit blood
•
there is blood in your bowel movement
or it is black and sticky like tar
•
skin rash or blisters with fever
•
unusual weight gain
•
swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more
information about NSAID medicines.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-
1088.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
•
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause
bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
•
Some of these NSAID medicines are sold in lower doses without a prescription (over –the –counter).
Talk to your healthcare provider before using over –the –counter NSAIDs for more than 10 days.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbiprofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with
oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with
lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less
than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of
heart attack or stroke.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
LAB-0609-1.0
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:37.730717
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018147s033s038s039s040s042lbl.pdf', 'application_number': 18147, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
11,171
|
FELDENE®
(piroxicam)
CAPSULES
10 mg and 20 mg
For Oral Use
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with
cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
• FELDENE is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur
at any time during use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
DESCRIPTION
FELDENE® contains piroxicam which is a member of the oxicam group of nonsteroidal
anti-inflammatory drugs (NSAIDs). Each maroon and blue capsule contains 10 mg piroxicam, each
maroon capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is
4-hydroxyl-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. Piroxicam
occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It
is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton
(pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). The molecular weight of piroxicam is 331.35.
Its molecular formula is C15H13N3O4S and it has the following structural formula:
O
C
NH
OH
N
CH3
S
O2
N
5
6
7
8
1
2
3
4
2′
6′
5′
4′
3′
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The inactive ingredients in FELDENE capsules include: Blue 1, Red 3, lactose, magnesium stearate,
sodium lauryl sulfate, starch.
CLINICAL PHARMACOLOGY
Pharmacodynamics
FELDENE is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory,
analgesic, and antipyretic activities in animal models. The mechanism of action of FELDENE, like that
of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase
inhibition.
Pharmacokinetics
Absorption: FELDENE is well absorbed following oral administration. Drug plasma concentrations
are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication.
The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations
throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single
20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum
drug plasma concentrations, after repeated daily ingestion of 20 mg FELDENE, usually stabilize at 3–
8 mcg/mL. Most patients approximate steady state plasma levels within 7–12 days. Higher levels,
which approximate steady state at two to three weeks, have been observed in patients in whom longer
plasma half-lives of piroxicam occurred.
With food there is a slight delay in the rate but not the extent of absorption following oral
administration. The concomitant administration of antacids (aluminum hydroxide or aluminum
hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of
orally administered piroxicam.
Distribution: The apparent volume of distribution of piroxicam is approximately 0.14 L/kg.
Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into
human milk. The presence in breast milk has been determined during initial and long-term conditions
(52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No
accumulation of piroxicam occurred in milk relative to that in plasma during treatment.
Metabolism: Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side
chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving
hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro
studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the
5′-hydroxy-piroxicam, the major metabolite (see Pharmacogenetics, and Special Populations, Poor
Metabolizers of CYP2C9 Substrates). The biotransformation products of piroxicam metabolism are
reported to not have any anti-inflammatory activity.
Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms
compared to normal metabolizer type subjects (see Pharmacogenetics, and Special Populations, Poor
Metabolizers of CYP2C9 Substrates).
Excretion: FELDENE and its biotransformation products are excreted in urine and feces, with about
twice as much appearing in the urine as in the feces. Approximately 5% of a FELDENE dose is
excreted unchanged. The plasma half-life (T½) for piroxicam is approximately 50 hours.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacogenetics: CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as
the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that
subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous
CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels,
respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following
administration of an oral single dose. The mean elimination half life values of piroxicam for subjects
with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than
subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3
genotype is 0% to 1% in the population at large; however, frequencies as high as 5.7% have been
reported in certain ethnic groups.
Special Populations
Pediatric: FELDENE has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been identified.
Hepatic Insufficiency: The effects of hepatic disease on FELDENE pharmacokinetics have not been
established. However, a substantial portion of FELDENE elimination occurs by hepatic metabolism.
Consequently, patients with hepatic disease may require reduced doses of FELDENE as compared to
patients with normal hepatic function.
Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9
metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as
warfarin and phenytoin) should be administered piroxicam with caution as they may have abnormally
high plasma levels due to reduced metabolic clearance.
Renal Insufficiency: FELDENE pharmacokinetics have been investigated in patients with renal
insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing
adjustments. However, the pharmacokinetic properties of FELDENE in patients with severe renal
insufficiency or those receiving hemodialysis are not known.
Other Information
In controlled clinical trials, the effectiveness of FELDENE has been established for both acute
exacerbations and long-term management of rheumatoid arthritis and osteoarthritis.
The therapeutic effects of FELDENE are evident early in the treatment of both diseases with a
progressive increase in response over several (8–12) weeks. Efficacy is seen in terms of pain relief and,
when present, subsidence of inflammation.
Doses of 20 mg/day FELDENE display a therapeutic effect comparable to therapeutic doses of aspirin,
with a lower incidence of minor gastrointestinal effects and tinnitus.
FELDENE has been administered concomitantly with fixed doses of gold and corticosteroids. The
existence of a “steroid-sparing” effect has not been adequately studied to date.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
FELDENE is indicated:
• For relief of the signs and symptoms of osteoarthritis.
• For relief of the signs and symptoms of rheumatoid arthritis.
CONTRAINDICATIONS
FELDENE is contraindicated in patients with known hypersensitivity to piroxicam.
FELDENE should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and
PRECAUTIONS: Preexisting Asthma).
FELDENE is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV
thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of
Ulceration, Bleeding, and Perforation).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypertension
NSAIDs, including FELDENE, can lead to onset of new hypertension or worsening of preexisting
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including FELDENE, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the
course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. FELDENE should be
used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including FELDENE, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4%
of patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk of GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, or
anticoagulants, longer duration of NSAID therapy; smoking; use of alcohol; older age; and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and, therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients,
alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of FELDENE in patients
with advanced renal disease. Therefore, treatment with FELDENE is not recommended in these
patients with advanced renal disease. If FELDENE therapy must be initiated, close monitoring of the
patient’s renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to
FELDENE. FELDENE should not be given to patients with the aspirin triad. This symptom complex
typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including FELDENE, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs and symptoms
of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
Other Hypersensitivity Reactions
A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness
have occasionally occurred in conjunction with the use of FELDENE. These include arthralgias,
pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis.
Pregnancy
In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
FELDENE cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of FELDENE in reducing fever and inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs,
including FELDENE. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more
times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant
hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of more severe hepatic reaction
while on therapy with FELDENE. If clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), FELDENE should be discontinued
(see ADVERSE REACTIONS).
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including FELDENE. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including FELDENE, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving FELDENE who may be adversely affected by alterations in platelet function, such as
those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Ophthalmologic Effects
Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is
recommended that patients who develop visual complaints during treatment with FELDENE have
ophthalmic evaluations.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with
aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since
cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, FELDENE should not be administered to
patients with this form of aspirin sensitivity and should be used with caution in patients with
preexisting asthma.
Reversible Delayed Ovulation
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including FELDENE,
may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility
in some women. Animal studies have shown that administration of prostaglandin synthesis inhibitors
has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small
studies in women taking NSAIDs have also shown a reversible delay in ovulation. Therefore, in
women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal
of NSAIDs, including FELDENE, should be considered.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• FELDENE, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may
result in hospitalization and even death. Although serious CV events can occur without warning
symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any
indicative signs or symptoms. Patients should be apprised of the importance of this follow-up
(see WARNINGS, CARDIOVASCULAR EFFECTS).
• FELDENE, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects,
such as ulcers and bleeding, which may result in hospitalization and even death. Although
serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should
be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia,
melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
• FELDENE, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious
skin reactions may occur without warning, patients should be alert for the signs and symptoms
of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask
for medical advice when observing any indicative signs or symptoms. Patients should be
advised to stop the drug immediately if they develop any type of rash and contact their
physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to
their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical
therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
• In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
• Advise females of reproductive potential who desire pregnancy that NSAIDs, including
Feldene, may be associated with a reversible delay in ovulation For women who have
difficulties conceiving, or who are undergoing investigation of infertility, use of piroxicam is
not recommended (see PRECAUTIONS--Reversible Delayed Ovulation).
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
Reference ID: 3708816
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consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.), or if abnormal liver tests persist or worsen, FELDENE should be discontinued.
Drug Interactions
Highly Protein Bound Drugs: FELDENE is highly protein bound and, therefore, might be expected to
displace other protein bound drugs. Physicians should closely monitor patients for a change in dosage
requirements when administering FELDENE to patients on other highly protein bound drugs.
Aspirin: When FELDENE is administered with aspirin, its protein binding is reduced, although the
clearance of free FELDENE is not altered. Plasma levels of piroxicam are depressed to approximately
80% of their normal values when FELDENE is administered (20 mg/day) in conjunction with aspirin
(3900 mg/day). The clinical significance of this interaction is not known; however, as with other
NSAIDs, concomitant administration of piroxicam and aspirin is not generally recommended because
of the potential for increased adverse effects.
Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution
should be used when NSAIDs are administered concomitantly with methotrexate.
ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly
with ACE-inhibitors.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Diuretics: Clinical studies, as well as postmarketing observations, have shown that FELDENE can
reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been
attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well
as to assure diuretic efficacy.
Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently,
subjects should be observed carefully for signs of lithium toxicity.
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both
drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Piroxicam has not been adequately evaluated for carcinogenicity.
Piroxicam was not mutagenic in an Ames bacterial reverse mutation assay, or in a dominant lethal
mutation assay in mice, and was not clastogenic in an in vivo chromosome aberration assay in mice.
Reference ID: 3708816
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Reproductive studies in which rats were administered piroxicam at doses of 2, 5, or 10 mg/kg/day (up
to 5 times the maximum recommended human dose [MRHD] of 20 mg based on mg/m2 body surface
area [BSA]) revealed no impairment of male or female fertility.
Pregnancy
Pregnancy Category C First and Second Trimester
Pregnancy Category D Third Trimester
There are no adequate and well-controlled studies of FELDENE (piroxicam) in pregnant women. Use
of NSAIDs, including FELDENE, during the third trimester of pregnancy increases the risk of
premature closure of the ductus arteriosus. All pregnancies, regardless of drug exposure, have a
background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. During the first and
second trimesters of pregnancy, use FELDENE only if the potential benefit justifies the potential risk
to the fetus. During the third trimester of pregnancy, the patient should be apprised of the potential
hazard to a fetus.
Pregnant rats administered piroxicam 2, 5, or 10 mg/kg/day during the period of organogenesis
(gestation days 6 to 15) demonstrated increased post-implantation losses with 5 and 10 mg/kg/day of
piroxicam (equivalent to 3 and 5 times the maximum recommended human dose [MRHD], of 20 mg
respectively, based on a mg/m2 body surface area [BSA]). There were no drug-related developmental
abnormalities noted in offspring. Gastrointestinal tract toxicity was increased in pregnant rats in the last
trimester of pregnancy compared to non-pregnant rats or rats in earlier trimesters of pregnancy.
Pregnant rabbits administered piroxicam 2, 5, or 10 mg/kg/day during the period of organogenesis
(gestation days 7 to 18) demonstrated no drug-related developmental abnormalities in offspring (up to
11 times the MRHD based on a mg/m2 BSA).
Based on animal data, prostaglandins have shown an important role in endometrial vascular
permeability, blastocyst implantation and decidualization. In animal studies, administration of
prostaglandin synthesis inhibitors such as piroxicam, have been shown to result in increased pre- and
post-implantation loss.
In a pre- and post-natal development study in which pregnant rats were administered piroxicam 2, 5, or
10 mg/kg/day on gestation day 15 through delivery and weaning of offspring, reduced weight gain and
death were observed in dams at 10 mg/kg/day starting gestation day 20 (5 times the MRHD based on a
mg/m2 BSA). Treated dams revealed peritonitis, adhesions, gastric bleeding, hemorrhagic enteritis and
dead fetuses in utero. Parturition was delayed in all piroxicam-treated groups, and there was an
increased incidence of stillbirth. Postnatal development could not be reliably assessed due to the
absence of maternal care secondary to severe maternal toxicity.
Labor and Delivery
The effects of FELDENE on labor or delivery in pregnant women are unknown. In rat studies with
piroxicam, as with other drugs known to inhibit prostaglandin synthesis, delayed parturition and an
increased incidence of stillbirth were noted at doses equivalent to the MRHD of piroxicam.
Nursing Mothers
Piroxicam is present in human milk at about 1% to 3% of the maternal concentration. No accumulation
of piroxicam occurred in milk relative to that in maternal plasma during treatment. The developmental
and health benefits of breastfeeding should be considered along with the mother’s clinical need for
Reference ID: 3708816
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FELDENE and any potential adverse effects on the breastfed child from the drug or from the
underlying maternal condition. Exercise caution when FELDENE is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
Most spontaneous reports of fatal GI events with NSAIDs are in the elderly or debilitated patients and,
therefore, care should be taken in treating this population. In addition to a past history of ulcer disease,
older age and poor general health status (among other factors) may increase the risk for GI bleeding. To
minimize the potential risk of an adverse GI event, the lowest effective dose should be used for the
shortest possible duration (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,
Bleeding, and Perforation).
As with all other NSAIDs, there is a risk of developing renal toxicity in patients in which renal
prostaglandins have a compensatory role in maintenance of renal perfusion. Discontinuation of
nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state
(see Warnings: Renal Effects).
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting a greater frequency of impaired drug elimination and of concomitant disease or
other drug therapy.
ADVERSE REACTIONS
In patients taking FELDENE or other NSAIDs, the most frequently reported adverse experiences
occurring in approximately 1–10% of patients are:
Cardiovascular System: Edema.
Digestive System: Anorexia, abdominal pain, constipation, diarrhea, dyspepsia, elevated liver
enzymes, flatulence, gross bleeding/perforation, heartburn, nausea, ulcers (gastric/duodenal),
vomiting.
Hemic and Lymphatic System: Anemia, increased bleeding time.
Nervous System: Dizziness, headache.
Skin and Appendages: Pruritus, rash.
Special Senses: Tinnitus.
Urogenital System: Abnormal renal function.
Additional adverse experiences reported occasionally include:
Body As a Whole: Fever, infection, sepsis.
Reference ID: 3708816
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Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope.
Digestive System: Dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice,
melena, rectal bleeding, stomatitis.
Hemic and Lymphatic System: Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial
rash, thrombocytopenia.
Metabolic and Nutritional: Weight changes, fluid retention.
Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness,
insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo.
Respiratory System: Asthma, dyspnea.
Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat.
Special Senses: Blurred vision.
Urogenital System: Cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic
syndrome, oliguria/polyuria, proteinuria, renal failure, glomerulonephritis.
Other adverse reactions which occur rarely are:
Body As a Whole: Anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic),
serum sickness.
Cardiovascular System: Arrhythmia, exacerbation of angina, hypotension, myocardial infarction,
palpitations, vasculitis.
Digestive System: Eructation, liver failure, pancreatitis.
Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia,
lymphadenopathy, pancytopenia.
Hypersensitivity: Positive ANA.
Metabolic and Nutritional: Hyperglycemia, hypoglycemia.
Nervous System: Akathisia, convulsions, coma, hallucinations, meningitis, mood alterations.
Respiratory: Respiratory depression, pneumonia.
Skin and Appendages: Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative
dermatitis, onycholysis, Stevens-Johnson Syndrome, urticaria, vesiculobullous reaction.
Special Senses: Conjunctivitis, hearing impairment, swollen eyes.
Reproductive system and breast disorders: Female fertility decreased.
Reference ID: 3708816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3708816
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OVERDOSAGE
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea,
vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal
bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but
are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may
occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There
are no specific antidotes. Emesis and/or activated charcoal (60–100 g in adults, 1–2 g/kg in children)
and/or osmotic cathartic may be indicated. The long plasma half-life of piroxicam should be considered
when treating an overdose with piroxicam. Experiments in dogs have demonstrated that the use of
multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam by more than
50% and systemic bioavailability by as much as 37% when activated charcoal is given as late as
6 hours after ingestion of piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or
hemoperfusion may not be useful due to high protein binding.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with FELDENE, the dose and frequency should be
adjusted to suit an individual patient’s needs.
For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is 20 mg given orally
once per day. If desired, the daily dose may be divided. Because of the long half-life of FELDENE,
steady-state blood levels are not reached for 7–12 days. Therefore, although the therapeutic effects of
FELDENE are evident early in treatment, there is a progressive increase in response over several weeks
and the effect of therapy should not be assessed for two weeks.
HOW SUPPLIED
FELDENE® Capsules for oral administration:
Bottles of 100: 10 mg (NDC 0069-3220-66) maroon and blue #322
Bottles of 100: 20 mg (NDC 0069-3230-66) maroon #323
This product’s label may have been updated. For current full prescribing information, please visit
www.pfizer.com.
Store below 86ºF (30ºC)
Reference ID: 3708816
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LAB-0206-13.3
Revised February 2015
Reference ID: 3708816
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Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.
This chance increases:
•
with longer use of NSAID medicines
•
in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft
(CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers
and bleeding:
•
can happen without warning symptoms
•
may cause death
The chance of a person getting an ulcer or bleeding increases with:
•
taking medicines called “corticosteroids” and “anticoagulants”
•
longer use
•
smoking
•
drinking alcohol
•
older age
•
having poor health
NSAID medicines should only be used:
•
exactly as prescribed
•
at the lowest dose possible for your treatment
•
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
•
different types of arthritis
•
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
•
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
•
for pain right before or after heart bypass surgery
Tell your healthcare provider:
•
about all of your medical conditions.
•
about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause
serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
•
if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
•
if you are breastfeeding. Talk to your doctor.
Reference ID: 3708816
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What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling (fluid retention)
•
kidney problems including kidney failure
•
bleeding and ulcers in the stomach and intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver failure
•
asthma attacks in people who have asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
Get emergency help right away if you have any of the following symptoms:
•
shortness of breath or trouble breathing
•
chest pain
•
weakness in one part or side of your body
•
slurred speech
•
swelling of the face or throat
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:
•
nausea
•
more tired or weaker than usual
•
itching
•
your skin or eyes look yellow
•
stomach pain
•
flu-like symptoms
•
vomit blood
•
there is blood in your bowel movement
or it is black and sticky like tar
•
skin rash or blisters with fever
•
unusual weight gain
•
swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more
information about NSAID medicines.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-
1088.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
•
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause
bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
•
Some of these NSAID medicines are sold in lower doses without a prescription (over –the –counter).
Talk to your healthcare provider before using over –the –counter NSAIDs for more than 10 days.
Reference ID: 3708816
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NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbiprofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with
oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with
lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less
than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of
heart attack or stroke.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
LAB-0609-1.0
Reference ID: 3708816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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FELDENE®
(piroxicam)
CAPSULES
10 mg and 20 mg
For Oral Use
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with
cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
• FELDENE® is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur
at any time during use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
DESCRIPTION
FELDENE® contains piroxicam which is a member of the oxicam group of nonsteroidal
anti-inflammatory drugs (NSAIDs). Each maroon and blue capsule contains 10 mg piroxicam, each
maroon capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is
4-hydroxyl-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. Piroxicam
occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It
is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton
(pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). The molecular weight of piroxicam is 331.35.
Its molecular formula is C15H13N3O4S and it has the following structural formula:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The inactive ingredients in FELDENE capsules include: Blue 1, Red 3, lactose, magnesium stearate,
sodium lauryl sulfate, starch.
CLINICAL PHARMACOLOGY
Pharmacodynamics
FELDENE is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory,
analgesic, and antipyretic activities in animal models. The mechanism of action of FELDENE, like that
of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase
inhibition.
Pharmacokinetics
Absorption: FELDENE is well absorbed following oral administration. Drug plasma concentrations
are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication.
The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations
throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single
20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum
drug plasma concentrations, after repeated daily ingestion of 20 mg FELDENE, usually stabilize at 3–
8 mcg/mL. Most patients approximate steady state plasma levels within 7–12 days. Higher levels,
which approximate steady state at two to three weeks, have been observed in patients in whom longer
plasma half-lives of piroxicam occurred.
With food there is a slight delay in the rate but not the extent of absorption following oral
administration. The concomitant administration of antacids (aluminum hydroxide or aluminum
hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of
orally administered piroxicam.
Distribution: The apparent volume of distribution of piroxicam is approximately 0.14 L/kg.
Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into
human milk. The presence in breast milk has been determined during initial and long-term conditions
(52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No
accumulation of piroxicam occurred in milk relative to that in plasma during treatment.
Metabolism: Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side
chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving
hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro
studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the
5′-hydroxy-piroxicam, the major metabolite (see Pharmacogenetics, and Special Populations, Poor
Metabolizers of CYP2C9 Substrates). The biotransformation products of piroxicam metabolism are
reported to not have any anti-inflammatory activity.
Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms
compared to normal metabolizer type subjects (see Pharmacogenetics, and Special Populations, Poor
Metabolizers of CYP2C9 Substrates).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Excretion: FELDENE and its biotransformation products are excreted in urine and feces, with about
twice as much appearing in the urine as in the feces. Approximately 5% of a FELDENE dose is
excreted unchanged. The plasma half-life (T½) for piroxicam is approximately 50 hours.
Pharmacogenetics: CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as
the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from one published report that included
nine subjects each with heterozygous CYP2C9*1/*2 and CYP2C9*1/*3 genotypes and one subject
with the homozygous CYP2C9*3/*3 genotype showed piroxicam systemic levels that were 1.7-, 1.7-
and 5.3-fold, respectively, higher compared to the 17 subjects with CYP2C9*1/*1 or normal
metabolizer genotype. The pharmacokinetics of piroxicam have not been evaluated in subjects with
other CYP2C9 polymorphisms, such as *5, *6, *9 and *11. It is estimated that the frequency of the
homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups.
Special Populations
Pediatric: FELDENE has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been identified.
Hepatic Insufficiency: The effects of hepatic disease on FELDENE pharmacokinetics have not been
established. However, a substantial portion of FELDENE elimination occurs by hepatic metabolism.
Consequently, patients with hepatic disease may require reduced doses of FELDENE as compared to
patients with normal hepatic function.
Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9
metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as
warfarin and phenytoin) should be administered piroxicam with caution as they may have abnormally
high plasma levels due to reduced metabolic clearance.
Renal Insufficiency: FELDENE pharmacokinetics have been investigated in patients with renal
insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing
adjustments. However, the pharmacokinetic properties of FELDENE in patients with severe renal
insufficiency or those receiving hemodialysis are not known.
Other Information
In controlled clinical trials, the effectiveness of FELDENE has been established for both acute
exacerbations and long-term management of rheumatoid arthritis and osteoarthritis.
The therapeutic effects of FELDENE are evident early in the treatment of both diseases with a
progressive increase in response over several (8–12) weeks. Efficacy is seen in terms of pain relief
and, when present, subsidence of inflammation.
Doses of 20 mg/day FELDENE display a therapeutic effect comparable to therapeutic doses of aspirin,
with a lower incidence of minor gastrointestinal effects and tinnitus.
FELDENE has been administered concomitantly with fixed doses of gold and corticosteroids. The
existence of a “steroid-sparing” effect has not been adequately studied to date.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
FELDENE is indicated:
• For relief of the signs and symptoms of osteoarthritis.
• For relief of the signs and symptoms of rheumatoid arthritis.
CONTRAINDICATIONS
FELDENE is contraindicated in patients with known hypersensitivity to piroxicam.
FELDENE should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and
PRECAUTIONS: Preexisting Asthma).
FELDENE is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of
Ulceration, Bleeding, and Perforation).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
Hypertension
NSAIDs, including FELDENE, can lead to onset of new hypertension or worsening of preexisting
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including FELDENE, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout
the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. FELDENE should be
used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including FELDENE, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4%
of patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk of GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and, therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients,
alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of FELDENE in patients
with advanced renal disease. Therefore, treatment with FELDENE is not recommended in these
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For current labeling information, please visit https://www.fda.gov/drugsatfda
patients with advanced renal disease. If FELDENE therapy must be initiated, close monitoring of the
patient’s renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to
FELDENE. FELDENE should not be given to patients with the aspirin triad. This symptom complex
typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including FELDENE, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs and symptoms
of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
Other Hypersensitivity Reactions
A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness
have occasionally occurred in conjunction with the use of FELDENE. These include arthralgias,
pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis.
Pregnancy
In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
FELDENE cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of FELDENE in reducing fever and inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs,
including FELDENE. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more
times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials
with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal
fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been
reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of more severe hepatic reaction
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For current labeling information, please visit https://www.fda.gov/drugsatfda
while on therapy with FELDENE. If clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), FELDENE should be discontinued
(see ADVERSE REACTIONS).
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including FELDENE. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including FELDENE, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and
reversible. Patients receiving FELDENE who may be adversely affected by alterations in platelet
function, such as those with coagulation disorders or patients receiving anticoagulants, should be
carefully monitored.
Ophthalmologic Effects
Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is
recommended that patients who develop visual complaints during treatment with FELDENE have
ophthalmic evaluations.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with
aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since
cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, FELDENE should not be administered to
patients with this form of aspirin sensitivity and should be used with caution in patients with
preexisting asthma.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
• FELDENE, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may
result in hospitalization and even death. Although serious CV events can occur without
warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness
of breath, weakness, slurring of speech, and should ask for medical advice when observing any
indicative signs or symptoms. Patients should be apprised of the importance of this follow-up
(see WARNINGS, CARDIOVASCULAR EFFECTS).
• FELDENE, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects,
such as ulcers and bleeding, which may result in hospitalization and even death. Although
serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should
be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia,
melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
• FELDENE, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious
skin reactions may occur without warning, patients should be alert for the signs and symptoms
of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should
ask for medical advice when observing any indicative signs or symptoms. Patients should be
advised to stop the drug immediately if they develop any type of rash and contact their
physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to
their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical
therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
• In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.), or if abnormal liver tests persist or worsen, FELDENE should be discontinued.
Drug Interactions
Highly Protein Bound Drugs: FELDENE is highly protein bound and, therefore, might be expected to
displace other protein bound drugs. Physicians should closely monitor patients for a change in dosage
requirements when administering FELDENE to patients on other highly protein bound drugs.
Aspirin: When FELDENE is administered with aspirin, its protein binding is reduced, although the
clearance of free FELDENE is not altered. Plasma levels of piroxicam are depressed to approximately
80% of their normal values when FELDENE is administered (20 mg/day) in conjunction with aspirin
(3900 mg/day). The clinical significance of this interaction is not known; however, as with other
NSAIDs, concomitant administration of piroxicam and aspirin is not generally recommended because
of the potential for increased adverse effects.
Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution
should be used when NSAIDs are administered concomitantly with methotrexate.
ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly
with ACE-inhibitors.
Diuretics: Clinical studies, as well as postmarketing observations, have shown that FELDENE can
reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been
attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well
as to assure diuretic efficacy.
Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium toxicity.
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both
drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Subacute, acute, and chronic toxicity studies have been carried out in rats, mice, dogs, and monkeys.
The pathology most often seen was that characteristically associated with the animal toxicology of
anti-inflammatory agents: renal papillary necrosis (see PRECAUTIONS) and gastrointestinal lesions.
Reproductive studies revealed no impairment of fertility in animals.
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Pregnancy
Teratogenic Effects: Pregnancy Category C
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of
developmental abnormalities. However, animal reproduction studies are not always predictive of
human response. There are no adequate and well-controlled studies in pregnant women. FELDENE is
not recommended for use in pregnant women since safety has not been established in humans.
FELDENE should be used in pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nonteratogenic Effects:
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided. In animal studies of FELDENE, gastrointestinal tract toxicity was increased in pregnant
females in the last trimester of pregnancy compared to nonpregnant females or females in earlier
trimesters of pregnancy.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of
FELDENE on labor and delivery in pregnant women are unknown.
Nursing Mothers
Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial
and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the
maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma
during treatment. FELDENE is not recommended for use in nursing mothers.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
Most spontaneous reports of fatal GI events with NSAIDs are in the elderly or debilitated patients and,
therefore, care should be taken in treating this population. In addition to a past history of ulcer disease,
older age and poor general health status (among other factors) may increase the risk for GI bleeding.
To minimize the potential risk of an adverse GI event, the lowest effective dose should be used for the
shortest possible duration (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,
Bleeding, and Perforation).
As with all other NSAIDs, there is a risk of developing renal toxicity in patients in which renal
prostaglandins have a compensatory role in maintenance of renal perfusion. Discontinuation of
nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state
(see Warnings: Renal Effects).
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of
the dosing range, reflecting a greater frequency of impaired drug elimination and of concomitant
disease or other drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
In patients taking FELDENE or other NSAIDs, the most frequently reported adverse experiences
occurring in approximately 1–10% of patients are:
Cardiovascular System: Edema.
Digestive System: Anorexia, abdominal pain, constipation, diarrhea, dyspepsia, elevated liver
enzymes, flatulence, gross bleeding/perforation, heartburn, nausea, ulcers (gastric/duodenal),
vomiting.
Hemic and Lymphatic System: Anemia, increased bleeding time.
Nervous System: Dizziness, headache.
Skin and Appendages: Pruritus, rash.
Special Senses: Tinnitus.
Urogenital System: Abnormal renal function.
Additional adverse experiences reported occasionally include:
Body As a Whole: Fever, infection, sepsis.
Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope.
Digestive System: Dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice,
melena, rectal bleeding, stomatitis.
Hemic and Lymphatic System: Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura,
petechial rash, thrombocytopenia.
Metabolic and Nutritional: Weight changes.
Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness,
insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo.
Respiratory System: Asthma, dyspnea.
Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat.
Special Senses: Blurred vision.
Urogenital System: Cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic
syndrome, oliguria/polyuria, proteinuria, renal failure.
Other adverse reactions which occur rarely are:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Body As a Whole: Anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic),
serum sickness.
Cardiovascular System: Arrhythmia, exacerbation of angina, hypotension, myocardial infarction,
palpitations, vasculitis.
Digestive System: Eructation, liver failure, pancreatitis.
Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia,
lymphadenopathy, pancytopenia.
Hypersensitivity: Positive ANA.
Metabolic and Nutritional: Hyperglycemia, hypoglycemia.
Nervous System: Akathisia, convulsions, coma, hallucinations, meningitis, mood alterations.
Respiratory: Respiratory depression, pneumonia.
Skin and Appendages: Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative
dermatitis, onycholysis, Stevens-Johnson Syndrome, urticaria, vesiculobullous reaction.
Special Senses: Conjunctivitis, hearing impairment, swollen eyes.
OVERDOSAGE
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea,
vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal
bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but
are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may
occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There
are no specific antidotes. Emesis and/or activated charcoal (60–100 g in adults, 1–2 g/kg in children)
and/or osmotic cathartic may be indicated. The long plasma half-life of piroxicam should be
considered when treating an overdose with piroxicam. Experiments in dogs have demonstrated that the
use of multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam by
more than 50% and systemic bioavailability by as much as 37% when activated charcoal is given as
late as 6 hours after ingestion of piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or
hemoperfusion may not be useful due to high protein binding.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with FELDENE, the dose and frequency should be
adjusted to suit an individual patient’s needs.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is 20 mg given orally
once per day. If desired, the daily dose may be divided. Because of the long half-life of FELDENE,
steady-state blood levels are not reached for 7–12 days. Therefore, although the therapeutic effects of
FELDENE are evident early in treatment, there is a progressive increase in response over several
weeks and the effect of therapy should not be assessed for two weeks.
HOW SUPPLIED
FELDENE® Capsules for oral administration:
Bottles of 100: 10 mg (NDC 0069-3220-66) maroon and blue #322
Bottles of 100: 20 mg (NDC 0069-3230-66) maroon #323
Rx only company logo
LAB-0206-8.1
Revised July 2010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018147s032lbl.pdf', 'application_number': 18147, 'submission_type': 'SUPPL ', 'submission_number': 32}
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NDA 18-147/S-029
Page 3
FELDENE®
(piroxicam)
CAPSULES
10 mg and 20 mg
For Oral Use
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patient’s
with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see
WARNINGS and CLINICAL TRIALS).
• FELDENE® is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAID’s cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur
at any time during use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (See WARNINGS).
DESCRIPTION
FELDENE® contains piroxicam which is a member of the oxicam group of nonsteroidal
anti-inflammatory drugs (NSAIDs). Each maroon and blue capsule contains 10 mg piroxicam, each
maroon capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is
4-hydroxyl-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. Piroxicam
occurs as a white crystalline solid, sparingly soluble in water, dilute acid and most organic solvents. It
is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton
(pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). The molecular weight of piroxicam is 331.35.
Its molecular formula is C15H13N3O4S and it has the following structural formula:
O
C
NH
OH
N
CH3
S
O2
N
5
6
7
8
1
2
3
4
2′
6′
5′
4′
3′
The inactive ingredients in FELDENE capsules include: Blue 1, Red 3, lactose, magnesium stearate,
sodium lauryl sulfate, starch.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 4
CLINICAL PHARMACOLOGY
Pharmacodynamics
FELDENE is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory,
analgesic, and antipyretic activities in animal models. The mechanism of action of FELDENE, like that
of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase
inhibition.
Pharmacokinetics
Absorption: FELDENE is well absorbed following oral administration. Drug plasma concentrations
are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication.
The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations
throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single
20-mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum
drug plasma concentrations, after repeated daily ingestion of 20 mg FELDENE, usually stabilize at
3-8 mcg/mL. Most patients approximate steady state plasma levels within 7-12 days. Higher levels,
which approximate steady state at two to three weeks, have been observed in patients in whom longer
plasma half-lives of piroxicam occurred.
With food there is a slight delay in the rate but not the extent of absorption following oral
administration. The concomitant administration of antacids (aluminum hydroxide or aluminum
hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of
orally administered piroxicam.
Distribution: The apparent volume of distribution of piroxicam is approximately 0.14 L/kg.
Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into
human milk. The presence in breast milk has been determined during initial and long-term conditions
(52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No
accumulation of piroxicam occurred in milk relative to that in plasma during treatment.
Metabolism: Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side
chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving
hydrolysis of the amide linkage, decarboxylation, ring contraction and N-demethylation. The
biotransformation products of piroxicam metabolism are reported to not have any anti-inflammatory
activity.
Excretion: FELDENE and its biotransformation products are excreted in urine and feces, with about
twice as much appearing in the urine as in the feces. Approximately 5% of a FELDENE dose is
excreted unchanged. The plasma half-life (T½) for piroxicam is approximately 50 hours.
Special Populations
Pediatric: FELDENE has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been identified.
Hepatic Insufficiency: The effects of hepatic disease on FELDENE pharmacokinetics have not been
established. However, a substantial portion of FELDENE elimination occurs by hepatic metabolism.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 5
Consequently, patients with hepatic disease may require reduced doses of FELDENE as compared to
patients with normal hepatic function.
Renal Insufficiency: FELDENE pharmacokinetics have been investigated in patients with renal
insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing
adjustments. However, the pharmacokinetic properties of FELDENE in patients with severe renal
insufficiency or those receiving hemodialysis are not known.
Other Information
In controlled clinical trials, the effectiveness of FELDENE has been established for both acute
exacerbations and long-term management of rheumatoid arthritis and osteoarthritis.
The therapeutic effects of FELDENE are evident early in the treatment of both diseases with a
progressive increase in response over several (8-12) weeks. Efficacy is seen in terms of pain relief and,
when present, subsidence of inflammation.
Doses of 20 mg/day FELDENE display a therapeutic effect comparable to therapeutic doses of aspirin,
with a lower incidence of minor gastrointestinal effects and tinnitus.
FELDENE has been administered concomitantly with fixed doses of gold and corticosteroids. The
existence of a “steroid-sparing” effect has not been adequately studied to date.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
FELDENE is indicated:
• For relief of the signs and symptoms of osteoarthritis.
• For relief of the signs and symptoms of rheumatoid arthritis.
CONTRAINDICATIONS
FELDENE is contraindicated in patients with known hypersensitivity to piroxicam.
FELDENE should not be given to patients who have experienced asthma, urticaria or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and
PRECAUTIONS, Preexisting Asthma).
FELDENE is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 6
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
Hypertension
NSAIDs, including FELDENE, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including FELDENE, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout
the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. FELDENE should be
used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding and Perforation
NSAIDs, including FELDENE, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI
adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of
patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 7
compared to patients with neither of these risk factors. Other factors that increase the risk of GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients,
alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of FELDENE in patients
with advanced renal disease. Therefore, treatment with FELDENE is not recommended in these
patients with advanced renal disease. If FELDENE therapy must be initiated, close monitoring of the
patient’s renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to
FELDENE. FELDENE should not be given to patients with the aspirin triad. This symptom complex
typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including FELDENE, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs an symptoms
of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 8
Other Hypersensitivity Reactions
A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness
have occasionally occurred in conjunction with the use of FELDENE. These include arthralgias,
pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis.
Pregnancy
In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
FELDENE cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of FELDENE in reducing fever and inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs
including FELDENE. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more
times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials
with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal
fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been
reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of more severe hepatic reaction
while on therapy with FELDENE. If clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), FELDENE should be discontinued.
(see ADVERSE REACTIONS).
Renal Effects
Caution should be used when initiating treatment with FELDENE in patients with considerable
dehydration. It is advisable to rehydrate patients first and then start therapy with FELDENE. Caution is
also recommended in patients with preexisting kidney disease (see WARNINGS: Advanced Renal
Disease).
Because of extensive renal excretion of piroxicam and its biotransformation products less than 5% of
the daily dose is excreted unchanged (see CLINICAL PHARMACOLOGY), lower doses of
piroxicam should be anticipated in patients with impaired renal function, and they should be carefully
monitored.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 9
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including FELDENE. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including FELDENE, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving FELDENE who may be adversely affected by alterations in platelet function, such
as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Ophthalmologic Effects
Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is
recommended that patients who develop visual complaints during treatment with FELDENE have
ophthalmic evaluations.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with
aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since
cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, FELDENE should not be administered to
patients with this form of aspirin sensitivity and should be used with caution in patients with
preexisting asthma.
Other Hypersensitivity Reactions
A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness
have occasionally occurred in conjunction with the use of FELDENE. These include arthralgias,
pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 10
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
1. FELDENE, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may
result in hospitalization and even death. Although serious CV events can occur without warning
symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any
indicative sign or symptoms. Patients should be apprised of the importance of this follow-up
(see WARNINGS, CARDIOVASCULAR EFFECTS).
2. FELDENE, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects,
such as ulcers and bleeding, which may result in hospitalization and even death. Although
serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should
be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia,
melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation).
3. FELDENE, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS and TEN, which may result in hospitalizations and even death. Although
serious skin reactions may occur without warning, patients should be alert for the signs and
symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and
should ask for medical advice when observing any indicative signs or symptoms. Patients
should be advised to stop the drug immediately if they develop any type of rash and contact
their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain, or edema to
their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical
therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it will may
cause premature closure of the ductus arteriosus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 11
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs of symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, FELDENE should be discontinued.
Drug Interactions
Highly Protein Bound Drugs: FELDENE is highly protein bound and, therefore, might be expected to
displace other protein bound drugs. Physicians should closely monitor patients for a change in dosage
requirements when administering FELDENE to patients on other highly protein bound drugs.
Aspirin: When FELDENE is administered with aspirin, its protein binding is reduced, although the
clearance of free FELDENE is not altered. Plasma levels of piroxicam are depressed to approximately
80% of their normal values when FELDENE is administered (20 mg/day) in conjunction with aspirin
(3900 mg/day). The clinical significance of this interaction is not known; however, as with other
NSAIDs, concomitant administration of piroxicam and aspirin is not generally recommended because
of the potential for increased adverse effects.
Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution
should be used when NSAIDs are administered concomitantly with methotrexate.
ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly
with ACE-inhibitors.
FurosemideDiuretics: Clinical studies, as well as postmarketing observations, have shown that
FELDENE can reduce the natriuretic effect of furosemide and thiazides in some patients. This
response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy
with NSAIDs, the patient should be observed closely for signs of renal failure (see
PRECAUTIONS:WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium toxicity.
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both
drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Subacute, acute and chronic toxicity studies have been carried out in rats, mice, dogs and monkeys.
The pathology most often seen was that characteristically associated with the animal toxicology of
anti-inflammatory agents: renal papillary necrosis (see PRECAUTIONS) and gastrointestinal lesions.
Reproductive studies revealed no impairment of fertility in animals.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 12
Pregnancy
Teratogenic Effects: Pregnancy Category C.
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental
abnormalities. However, animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies in pregnant women. FELDENE is not recommended
for use in pregnant women since safety has not been established in humans. Feldene should be used in
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects:
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided. In animal studies of FELDENE, gastrointestinal tract toxicity was increased in pregnant
females in the last trimester of pregnancy compared to nonpregnant females or females in earlier
trimesters of pregnancy.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of
FELDENE on labor and delivery in pregnant women are unknown.
Nursing Mothers
Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial
and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the
maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma
during treatment. FELDENE is not recommended for use in nursing mothers.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
Most spontaneous reports of fatal GI events with NSAIDs are in the elderly or debilitated patients and,
therefore, care should be taken in treating this population. In addition to a past history of ulcer disease,
older age and poor general health status (among other factors) may increase the risk for GI bleeding.
To minimize the potential risk of an adverse GI event, the lowest effective dose should be used for the
shortest possible duration (see WARNINGS, Gastrointestinal Effects – Risk of GI Ulceration,
Bleeding and Perforation).
As with all other NSAIDs, there is a risk of developing renal toxicity in patients in which renal
prostaglandins have a compensatory role in maintenance of renal perfusion. Discontinuation of
nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state
(see PRECAUTIONS, Renal Effects).
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of
the dosing range, reflecting a greater frequency of impaired drug elimination and of concomitant
disease or other drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 13
ADVERSE REACTIONS
In patients taking FELDENE or other NSAIDs, the most frequently reported adverse experiences
occurring in approximately 1-10% of patients are:
Cardiovascular System: Edema.
Digestive System: Anorexia, abdominal pain, constipation, diarrhea, dyspepsia, elevated liver
enzymes, flatulence, gross bleeding/perforation, heartburn, nausea, ulcers (gastric/duodenal),
vomiting.
Hemic and Lymphatic System: Anemia, increased bleeding time.
Nervous System: Dizziness, headache.
Skin and Appendages: Pruritus, rash.
Special Senses: Tinnitus.
Urogenital System: Abnormal renal function.
Additional adverse experiences reported occasionally include:
Body As a Whole: Fever, infection, sepsis.
Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope.
Digestive System: Dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice,
melena, rectal bleeding, stomatitis.
Hemic and Lymphatic System: Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial
rash, thrombocytopenia.
Metabolic and Nutritional: Weight changes.
Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness,
insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo.
Respiratory System: Asthma, dyspnea.
Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat.
Special Senses: Blurred vision.
Urogenital System: Cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic
syndrome, oliguria/polyuria, proteinuria, renal failure.
Other adverse reactions which occur rarely are:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 14
Body As a Whole: Anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic),
serum sickness.
Cardiovascular System: Arrhythmia, exacerbation of angina, hypotension, myocardial infarction,
palpitations, vasculitis.
Digestive System: Eructation, liver failure, pancreatitis.
Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia,
lymphadenopathy, pancytopenia.
Hypersensitivity: Positive ANA.
Metabolic and Nutritional: Hyperglycemia, hypoglycemia.
Nervous System: Akathisia, convulsions, coma, hallucinations, meningitis, mood alterations.
Respiratory: Respiratory depression, pneumonia.
Skin and Appendages: Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative
dermatitis, onycholysis, Stevens-Johnson syndrome, urticaria, vesiculobullous reaction.
Special Senses: Conjunctivitis, hearing impairment, swollen eyes.
OVERDOSAGE
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea,
vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal
bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but
are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may
occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There
are no specific antidotes. Emesis and/or activated charcoal (60-100 g in adults, 1-2 g/kg in children)
and/or osmotic cathartic may be indicated. The long plasma half-life of piroxicam should be
considered when treating an overdose with piroxicam. Experiments in dogs have demonstrated that the
use of multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam by more
than 50% and systemic bioavailability by as much as 37% when activated charcoal is given as late as
6 hours after ingestion of piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or
hemoperfusion may not be useful due to high protein binding.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with FELDENE, the dose and frequency should be
adjusted to suit an individual patient’s needs.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 15
For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is 20 mg given orally
once per day. If desired, the daily dose may be divided. Because of the long half-life of FELDENE,
steady-state blood levels are not reached for 7-12 days. Therefore, although the therapeutic effects of
FELDENE are evident early in treatment, there is a progressive increase in response over several
weeks and the effect of therapy should not be assessed for two weeks.
HOW SUPPLIED
FELDENE® Capsules for oral administration:
Bottles of 100:
20 mg (NDC 0069-3230-66) maroon #323
Bottles of 500:
20 mg (NDC 0069-3230-73) maroon #323
Rx only
©2005 PFIZER INC
Distributed by:
LAB 0206-XX
Revised July 2005
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
Pfizer Labs
Division of Pfizer Inc, NY, NY
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 16
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 17
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and sticky
like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-147/S-029
Page 18
Generic Name
Tradename
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:44:37.919583
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018147s029lbl.pdf', 'application_number': 18147, 'submission_type': 'SUPPL ', 'submission_number': 29}
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11,172
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FELDENE®
(piroxicam)
CAPSULES
10 mg and 20 mg
For Oral Use
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with
cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
• FELDENE is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur
at any time during use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
DESCRIPTION
FELDENE® contains piroxicam which is a member of the oxicam group of nonsteroidal
anti-inflammatory drugs (NSAIDs). Each maroon and blue capsule contains 10 mg piroxicam, each
maroon capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is
4-hydroxyl-2-methyl-N-2-pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. Piroxicam
occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It
is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton
(pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). The molecular weight of piroxicam is 331.35.
Its molecular formula is C15H13N3O4S and it has the following structural formula:
O
C
NH
OH
N
CH3
S
O2
N
5
6
7
8
1
2
3
4
2′
6′
5′
4′
3′
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The inactive ingredients in FELDENE capsules include: Blue 1, Red 3, lactose, magnesium stearate,
sodium lauryl sulfate, starch.
CLINICAL PHARMACOLOGY
Pharmacodynamics
FELDENE is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory,
analgesic, and antipyretic activities in animal models. The mechanism of action of FELDENE, like that
of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase
inhibition.
Pharmacokinetics
Absorption: FELDENE is well absorbed following oral administration. Drug plasma concentrations
are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication.
The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations
throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single
20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum
drug plasma concentrations, after repeated daily ingestion of 20 mg FELDENE, usually stabilize at 3–
8 mcg/mL. Most patients approximate steady state plasma levels within 7–12 days. Higher levels,
which approximate steady state at two to three weeks, have been observed in patients in whom longer
plasma half-lives of piroxicam occurred.
With food there is a slight delay in the rate but not the extent of absorption following oral
administration. The concomitant administration of antacids (aluminum hydroxide or aluminum
hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of
orally administered piroxicam.
Distribution: The apparent volume of distribution of piroxicam is approximately 0.14 L/kg.
Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into
human milk. The presence in breast milk has been determined during initial and long-term conditions
(52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No
accumulation of piroxicam occurred in milk relative to that in plasma during treatment.
Metabolism: Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side
chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving
hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro
studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the
5′-hydroxy-piroxicam, the major metabolite (see Pharmacogenetics, and Special Populations, Poor
Metabolizers of CYP2C9 Substrates). The biotransformation products of piroxicam metabolism are
reported to not have any anti-inflammatory activity.
Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms
compared to normal metabolizer type subjects (see Pharmacogenetics, and Special Populations, Poor
Metabolizers of CYP2C9 Substrates).
Excretion: FELDENE and its biotransformation products are excreted in urine and feces, with about
twice as much appearing in the urine as in the feces. Approximately 5% of a FELDENE dose is
excreted unchanged. The plasma half-life (T½) for piroxicam is approximately 50 hours.
Reference ID: 3708816
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Pharmacogenetics: CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as
the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that
subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous
CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels,
respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following
administration of an oral single dose. The mean elimination half life values of piroxicam for subjects
with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than
subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3
genotype is 0% to 1% in the population at large; however, frequencies as high as 5.7% have been
reported in certain ethnic groups.
Special Populations
Pediatric: FELDENE has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been identified.
Hepatic Insufficiency: The effects of hepatic disease on FELDENE pharmacokinetics have not been
established. However, a substantial portion of FELDENE elimination occurs by hepatic metabolism.
Consequently, patients with hepatic disease may require reduced doses of FELDENE as compared to
patients with normal hepatic function.
Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9
metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as
warfarin and phenytoin) should be administered piroxicam with caution as they may have abnormally
high plasma levels due to reduced metabolic clearance.
Renal Insufficiency: FELDENE pharmacokinetics have been investigated in patients with renal
insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing
adjustments. However, the pharmacokinetic properties of FELDENE in patients with severe renal
insufficiency or those receiving hemodialysis are not known.
Other Information
In controlled clinical trials, the effectiveness of FELDENE has been established for both acute
exacerbations and long-term management of rheumatoid arthritis and osteoarthritis.
The therapeutic effects of FELDENE are evident early in the treatment of both diseases with a
progressive increase in response over several (8–12) weeks. Efficacy is seen in terms of pain relief and,
when present, subsidence of inflammation.
Doses of 20 mg/day FELDENE display a therapeutic effect comparable to therapeutic doses of aspirin,
with a lower incidence of minor gastrointestinal effects and tinnitus.
FELDENE has been administered concomitantly with fixed doses of gold and corticosteroids. The
existence of a “steroid-sparing” effect has not been adequately studied to date.
Reference ID: 3708816
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INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
FELDENE is indicated:
• For relief of the signs and symptoms of osteoarthritis.
• For relief of the signs and symptoms of rheumatoid arthritis.
CONTRAINDICATIONS
FELDENE is contraindicated in patients with known hypersensitivity to piroxicam.
FELDENE should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and
PRECAUTIONS: Preexisting Asthma).
FELDENE is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV
thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of
Ulceration, Bleeding, and Perforation).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
Reference ID: 3708816
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Hypertension
NSAIDs, including FELDENE, can lead to onset of new hypertension or worsening of preexisting
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including FELDENE, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the
course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. FELDENE should be
used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including FELDENE, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4%
of patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk of GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, or
anticoagulants, longer duration of NSAID therapy; smoking; use of alcohol; older age; and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and, therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients,
alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
Reference ID: 3708816
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of FELDENE in patients
with advanced renal disease. Therefore, treatment with FELDENE is not recommended in these
patients with advanced renal disease. If FELDENE therapy must be initiated, close monitoring of the
patient’s renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to
FELDENE. FELDENE should not be given to patients with the aspirin triad. This symptom complex
typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including FELDENE, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs and symptoms
of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
Other Hypersensitivity Reactions
A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness
have occasionally occurred in conjunction with the use of FELDENE. These include arthralgias,
pruritus, fever, fatigue, and rash including vesiculobullous reactions and exfoliative dermatitis.
Pregnancy
In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
FELDENE cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of FELDENE in reducing fever and inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs,
including FELDENE. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more
times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials
Reference ID: 3708816
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with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant
hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of more severe hepatic reaction
while on therapy with FELDENE. If clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), FELDENE should be discontinued
(see ADVERSE REACTIONS).
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including FELDENE. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including FELDENE, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving FELDENE who may be adversely affected by alterations in platelet function, such as
those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Ophthalmologic Effects
Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is
recommended that patients who develop visual complaints during treatment with FELDENE have
ophthalmic evaluations.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with
aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since
cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, FELDENE should not be administered to
patients with this form of aspirin sensitivity and should be used with caution in patients with
preexisting asthma.
Reversible Delayed Ovulation
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including FELDENE,
may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility
in some women. Animal studies have shown that administration of prostaglandin synthesis inhibitors
has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small
studies in women taking NSAIDs have also shown a reversible delay in ovulation. Therefore, in
women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal
of NSAIDs, including FELDENE, should be considered.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
Reference ID: 3708816
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• FELDENE, like other NSAIDs, may cause CV side effects, such as MI or stroke, which may
result in hospitalization and even death. Although serious CV events can occur without warning
symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any
indicative signs or symptoms. Patients should be apprised of the importance of this follow-up
(see WARNINGS, CARDIOVASCULAR EFFECTS).
• FELDENE, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects,
such as ulcers and bleeding, which may result in hospitalization and even death. Although
serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should
be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia,
melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
• FELDENE, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious
skin reactions may occur without warning, patients should be alert for the signs and symptoms
of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask
for medical advice when observing any indicative signs or symptoms. Patients should be
advised to stop the drug immediately if they develop any type of rash and contact their
physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to
their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical
therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
• In late pregnancy, as with other NSAIDs, FELDENE should be avoided because it may cause
premature closure of the ductus arteriosus.
• Advise females of reproductive potential who desire pregnancy that NSAIDs, including
Feldene, may be associated with a reversible delay in ovulation For women who have
difficulties conceiving, or who are undergoing investigation of infertility, use of piroxicam is
not recommended (see PRECAUTIONS--Reversible Delayed Ovulation).
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
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consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.), or if abnormal liver tests persist or worsen, FELDENE should be discontinued.
Drug Interactions
Highly Protein Bound Drugs: FELDENE is highly protein bound and, therefore, might be expected to
displace other protein bound drugs. Physicians should closely monitor patients for a change in dosage
requirements when administering FELDENE to patients on other highly protein bound drugs.
Aspirin: When FELDENE is administered with aspirin, its protein binding is reduced, although the
clearance of free FELDENE is not altered. Plasma levels of piroxicam are depressed to approximately
80% of their normal values when FELDENE is administered (20 mg/day) in conjunction with aspirin
(3900 mg/day). The clinical significance of this interaction is not known; however, as with other
NSAIDs, concomitant administration of piroxicam and aspirin is not generally recommended because
of the potential for increased adverse effects.
Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution
should be used when NSAIDs are administered concomitantly with methotrexate.
ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly
with ACE-inhibitors.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Diuretics: Clinical studies, as well as postmarketing observations, have shown that FELDENE can
reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been
attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well
as to assure diuretic efficacy.
Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently,
subjects should be observed carefully for signs of lithium toxicity.
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both
drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Piroxicam has not been adequately evaluated for carcinogenicity.
Piroxicam was not mutagenic in an Ames bacterial reverse mutation assay, or in a dominant lethal
mutation assay in mice, and was not clastogenic in an in vivo chromosome aberration assay in mice.
Reference ID: 3708816
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Reproductive studies in which rats were administered piroxicam at doses of 2, 5, or 10 mg/kg/day (up
to 5 times the maximum recommended human dose [MRHD] of 20 mg based on mg/m2 body surface
area [BSA]) revealed no impairment of male or female fertility.
Pregnancy
Pregnancy Category C First and Second Trimester
Pregnancy Category D Third Trimester
There are no adequate and well-controlled studies of FELDENE (piroxicam) in pregnant women. Use
of NSAIDs, including FELDENE, during the third trimester of pregnancy increases the risk of
premature closure of the ductus arteriosus. All pregnancies, regardless of drug exposure, have a
background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. During the first and
second trimesters of pregnancy, use FELDENE only if the potential benefit justifies the potential risk
to the fetus. During the third trimester of pregnancy, the patient should be apprised of the potential
hazard to a fetus.
Pregnant rats administered piroxicam 2, 5, or 10 mg/kg/day during the period of organogenesis
(gestation days 6 to 15) demonstrated increased post-implantation losses with 5 and 10 mg/kg/day of
piroxicam (equivalent to 3 and 5 times the maximum recommended human dose [MRHD], of 20 mg
respectively, based on a mg/m2 body surface area [BSA]). There were no drug-related developmental
abnormalities noted in offspring. Gastrointestinal tract toxicity was increased in pregnant rats in the last
trimester of pregnancy compared to non-pregnant rats or rats in earlier trimesters of pregnancy.
Pregnant rabbits administered piroxicam 2, 5, or 10 mg/kg/day during the period of organogenesis
(gestation days 7 to 18) demonstrated no drug-related developmental abnormalities in offspring (up to
11 times the MRHD based on a mg/m2 BSA).
Based on animal data, prostaglandins have shown an important role in endometrial vascular
permeability, blastocyst implantation and decidualization. In animal studies, administration of
prostaglandin synthesis inhibitors such as piroxicam, have been shown to result in increased pre- and
post-implantation loss.
In a pre- and post-natal development study in which pregnant rats were administered piroxicam 2, 5, or
10 mg/kg/day on gestation day 15 through delivery and weaning of offspring, reduced weight gain and
death were observed in dams at 10 mg/kg/day starting gestation day 20 (5 times the MRHD based on a
mg/m2 BSA). Treated dams revealed peritonitis, adhesions, gastric bleeding, hemorrhagic enteritis and
dead fetuses in utero. Parturition was delayed in all piroxicam-treated groups, and there was an
increased incidence of stillbirth. Postnatal development could not be reliably assessed due to the
absence of maternal care secondary to severe maternal toxicity.
Labor and Delivery
The effects of FELDENE on labor or delivery in pregnant women are unknown. In rat studies with
piroxicam, as with other drugs known to inhibit prostaglandin synthesis, delayed parturition and an
increased incidence of stillbirth were noted at doses equivalent to the MRHD of piroxicam.
Nursing Mothers
Piroxicam is present in human milk at about 1% to 3% of the maternal concentration. No accumulation
of piroxicam occurred in milk relative to that in maternal plasma during treatment. The developmental
and health benefits of breastfeeding should be considered along with the mother’s clinical need for
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FELDENE and any potential adverse effects on the breastfed child from the drug or from the
underlying maternal condition. Exercise caution when FELDENE is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
Most spontaneous reports of fatal GI events with NSAIDs are in the elderly or debilitated patients and,
therefore, care should be taken in treating this population. In addition to a past history of ulcer disease,
older age and poor general health status (among other factors) may increase the risk for GI bleeding. To
minimize the potential risk of an adverse GI event, the lowest effective dose should be used for the
shortest possible duration (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration,
Bleeding, and Perforation).
As with all other NSAIDs, there is a risk of developing renal toxicity in patients in which renal
prostaglandins have a compensatory role in maintenance of renal perfusion. Discontinuation of
nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state
(see Warnings: Renal Effects).
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting a greater frequency of impaired drug elimination and of concomitant disease or
other drug therapy.
ADVERSE REACTIONS
In patients taking FELDENE or other NSAIDs, the most frequently reported adverse experiences
occurring in approximately 1–10% of patients are:
Cardiovascular System: Edema.
Digestive System: Anorexia, abdominal pain, constipation, diarrhea, dyspepsia, elevated liver
enzymes, flatulence, gross bleeding/perforation, heartburn, nausea, ulcers (gastric/duodenal),
vomiting.
Hemic and Lymphatic System: Anemia, increased bleeding time.
Nervous System: Dizziness, headache.
Skin and Appendages: Pruritus, rash.
Special Senses: Tinnitus.
Urogenital System: Abnormal renal function.
Additional adverse experiences reported occasionally include:
Body As a Whole: Fever, infection, sepsis.
Reference ID: 3708816
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Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope.
Digestive System: Dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice,
melena, rectal bleeding, stomatitis.
Hemic and Lymphatic System: Ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial
rash, thrombocytopenia.
Metabolic and Nutritional: Weight changes, fluid retention.
Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness,
insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo.
Respiratory System: Asthma, dyspnea.
Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat.
Special Senses: Blurred vision.
Urogenital System: Cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic
syndrome, oliguria/polyuria, proteinuria, renal failure, glomerulonephritis.
Other adverse reactions which occur rarely are:
Body As a Whole: Anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic),
serum sickness.
Cardiovascular System: Arrhythmia, exacerbation of angina, hypotension, myocardial infarction,
palpitations, vasculitis.
Digestive System: Eructation, liver failure, pancreatitis.
Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia,
lymphadenopathy, pancytopenia.
Hypersensitivity: Positive ANA.
Metabolic and Nutritional: Hyperglycemia, hypoglycemia.
Nervous System: Akathisia, convulsions, coma, hallucinations, meningitis, mood alterations.
Respiratory: Respiratory depression, pneumonia.
Skin and Appendages: Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative
dermatitis, onycholysis, Stevens-Johnson Syndrome, urticaria, vesiculobullous reaction.
Special Senses: Conjunctivitis, hearing impairment, swollen eyes.
Reproductive system and breast disorders: Female fertility decreased.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea,
vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal
bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but
are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may
occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There
are no specific antidotes. Emesis and/or activated charcoal (60–100 g in adults, 1–2 g/kg in children)
and/or osmotic cathartic may be indicated. The long plasma half-life of piroxicam should be considered
when treating an overdose with piroxicam. Experiments in dogs have demonstrated that the use of
multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam by more than
50% and systemic bioavailability by as much as 37% when activated charcoal is given as late as
6 hours after ingestion of piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or
hemoperfusion may not be useful due to high protein binding.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of FELDENE and other treatment options before
deciding to use FELDENE. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with FELDENE, the dose and frequency should be
adjusted to suit an individual patient’s needs.
For the relief of rheumatoid arthritis and osteoarthritis, the recommended dose is 20 mg given orally
once per day. If desired, the daily dose may be divided. Because of the long half-life of FELDENE,
steady-state blood levels are not reached for 7–12 days. Therefore, although the therapeutic effects of
FELDENE are evident early in treatment, there is a progressive increase in response over several weeks
and the effect of therapy should not be assessed for two weeks.
HOW SUPPLIED
FELDENE® Capsules for oral administration:
Bottles of 100: 10 mg (NDC 0069-3220-66) maroon and blue #322
Bottles of 100: 20 mg (NDC 0069-3230-66) maroon #323
This product’s label may have been updated. For current full prescribing information, please visit
www.pfizer.com.
Store below 86ºF (30ºC)
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LAB-0206-13.3
Revised February 2015
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.
This chance increases:
•
with longer use of NSAID medicines
•
in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft
(CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers
and bleeding:
•
can happen without warning symptoms
•
may cause death
The chance of a person getting an ulcer or bleeding increases with:
•
taking medicines called “corticosteroids” and “anticoagulants”
•
longer use
•
smoking
•
drinking alcohol
•
older age
•
having poor health
NSAID medicines should only be used:
•
exactly as prescribed
•
at the lowest dose possible for your treatment
•
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
•
different types of arthritis
•
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
•
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
•
for pain right before or after heart bypass surgery
Tell your healthcare provider:
•
about all of your medical conditions.
•
about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause
serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
•
if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
•
if you are breastfeeding. Talk to your doctor.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling (fluid retention)
•
kidney problems including kidney failure
•
bleeding and ulcers in the stomach and intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver failure
•
asthma attacks in people who have asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
Get emergency help right away if you have any of the following symptoms:
•
shortness of breath or trouble breathing
•
chest pain
•
weakness in one part or side of your body
•
slurred speech
•
swelling of the face or throat
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:
•
nausea
•
more tired or weaker than usual
•
itching
•
your skin or eyes look yellow
•
stomach pain
•
flu-like symptoms
•
vomit blood
•
there is blood in your bowel movement
or it is black and sticky like tar
•
skin rash or blisters with fever
•
unusual weight gain
•
swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more
information about NSAID medicines.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-
1088.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
•
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause
bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
•
Some of these NSAID medicines are sold in lower doses without a prescription (over –the –counter).
Talk to your healthcare provider before using over –the –counter NSAIDs for more than 10 days.
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbiprofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with
oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with
lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less
than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of
heart attack or stroke.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
LAB-0609-1.0
Reference ID: 3708816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:38.076210
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018147s033s038s039s040s042lbl.pdf', 'application_number': 18147, 'submission_type': 'SUPPL ', 'submission_number': 42}
|
11,173
|
Loniten®
minoxidil tablets, USP
WARNINGS
LONITEN Tablets contain the powerful antihypertensive agent, minoxidil, which may
produce serious adverse effects. It can cause pericardial effusion, occasionally
progressing to tamponade, and angina pectoris may be exacerbated. LONITEN should be
reserved for hypertensive patients who do not respond adequately to maximum
therapeutic doses of a diuretic and two other antihypertensive agents.
In experimental animals, minoxidil caused several kinds of myocardial lesions as well as
other adverse cardiac effects (see Cardiac Lesions in Animals).
LONITEN must be administered under close supervision, usually concomitantly with
therapeutic doses of a beta-adrenergic blocking agent to prevent tachycardia and
increased myocardial workload. It must also usually be given with a diuretic, frequently
one acting in the ascending limb of the loop of Henle, to prevent serious fluid
accumulation. Patients with malignant hypertension and those already receiving
guanethidine (see WARNINGS) should be hospitalized when LONITEN is first
administered so that they can be monitored to avoid too rapid, or large orthostatic,
decreases in blood pressure.
DESCRIPTION
LONITEN Tablets contain minoxidil, an antihypertensive peripheral vasodilator.
Minoxidil occurs as a white or off-white, odorless, crystalline solid that is soluble in
water to the extent of approximately 2 mg/mL, is readily soluble in propylene glycol or
ethanol, and is almost insoluble in acetone, chloroform or ethyl acetate. The chemical
name for minoxidil is 2,4-pyrimidinediamine,6-(1-piperidinyl)-, 3-oxide (mw=209.25).
The structural formula is represented at right: structural formula
LONITEN Tablets for oral administration contain either 2.5 mg or 10 mg of minoxidil.
Inactive ingredients: cellulose, corn starch, lactose, magnesium stearate, silicon dioxide.
Reference ID: 3685475
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
1. General Pharmacologic Properties
Minoxidil is an orally effective direct acting peripheral vasodilator that reduces elevated
systolic and diastolic blood pressure by decreasing peripheral vascular resistance.
Microcirculatory blood flow in animals is enhanced or maintained in all systemic
vascular beds. In man, forearm and renal vascular resistance decline; forearm blood flow
increases while renal blood flow and glomerular filtration rate are preserved.
Because it causes peripheral vasodilation, minoxidil elicits a number of predictable
reactions. Reduction of peripheral arteriolar resistance and the associated fall in blood
pressure trigger sympathetic, vagal inhibitory, and renal homeostatic mechanisms,
including an increase in renin secretion, that lead to increased cardiac rate and output and
salt and water retention. These adverse effects can usually be minimized by concomitant
administration of a diuretic and a beta-adrenergic blocking agent or other sympathetic
nervous system suppressant.
Minoxidil does not interfere with vasomotor reflexes and therefore does not produce
orthostatic hypotension. The drug does not enter the central nervous system in
experimental animals in significant amounts, and it does not affect CNS function in man.
2. Effects on Blood Pressure and Target Organs
The extent and time-course of blood pressure reduction by minoxidil do not correspond
closely to its concentration in plasma. After an effective single oral dose, blood pressure
usually starts to decline within one-half hour, reaches a minimum between 2 and 3 hours
and recovers at an arithmetically linear rate of about 30%/day. The total duration of effect
is approximately 75 hours. When minoxidil is administered chronically, once or twice a
day, the time required to achieve maximum effect on blood pressure with a given daily
dose is inversely related to the size of the dose. Thus, maximum effect is achieved on 10
mg/day within 7 days, on 20 mg/day within 5 days, and on 40 mg/day within 3 days.
The blood pressure response to minoxidil is linearly related to the logarithm of the dose
administered. The slope of this log-linear dose-response relationship is proportional to the
extent of hypertension and approaches zero at a supine diastolic blood pressure of
approximately 85 mm Hg.
When used in severely hypertensive patients resistant to other therapy, frequently with an
accompanying diuretic and beta-blocker, LONITEN Tablets usually decreased the blood
pressure and reversed encephalopathy and retinopathy.
3. Absorption and Metabolism
Minoxidil is at least 90% absorbed from the GI tract in experimental animals and man.
Plasma levels of the parent drug reach maximum within the first hour and decline rapidly
thereafter. The average plasma half-life in man is 4.2 hours. Approximately 90% of the
administered drug is metabolized, predominantly by conjugation with glucuronic acid at
the N-oxide position in the pyrimidine ring, but also by conversion to more polar
products. Known metabolites exert much less pharmacologic effect than minoxidil itself;
Reference ID: 3685475
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all are excreted principally in the urine. Minoxidil does not bind to plasma proteins and
does not cross the blood brain barrier. Its renal clearance corresponds to the glomerular
filtration rate. In the absence of functional renal tissue, minoxidil and its metabolites can
be removed by hemodialysis.
4. Cardiac Lesions in Animals
Minoxidil produces several cardiac lesions in animals. Some are characteristic of agents
that cause tachycardia and diastolic hypotension (beta-agonists like isoproterenol, arterial
dilators like hydralazine) while others are produced by a narrower range of agents with
arterial dilating properties. The significance of these lesions for humans is not clear, as
they have not been recognized in patients treated with oral minoxidil at systemically
active doses, despite formal review of over 150 autopsies of treated patients.
(a) Papillary muscle/subendocardial necrosis
The most characteristic lesion of minoxidil, seen in rat, dog, and minipig (but not
monkeys) is focal necrosis of the papillary muscle and subendocardial areas of the
left ventricle. These lesions appear rapidly, within a few days of treatment with
doses of 0.5 to 10 mg/kg/day in the dog and minipig, and are not progressive,
although they leave residual scars. They are similar to lesions produced by other
peripheral arterial dilators, by theobromine, and by beta-adrenergic receptor
agonists such as isoproterenol, epinephrine, and albuterol. The lesions are thought
to reflect ischemia provoked by increased oxygen demand (tachycardia, increased
cardiac output) and relative decrease in coronary flow (decreased diastolic
pressure and decreased time in diastole) caused by the vasodilatory effects of
these agents coupled with reflex or directly induced tachycardia.
(b) Hemorrhagic lesions
After acute oral minoxidil treatment (0.5 to 10 mg/kg/day) in dogs and minipigs,
hemorrhagic lesions are seen in many parts of the heart, mainly in the epicardium,
endocardium, and walls of small coronary arteries and arterioles. In minipigs the
lesions occur primarily in the left atrium while in dogs they are most prominent in
the right atrium, frequently appearing as grossly visible hemorrhagic lesions. With
exposure of 1–20 mg/kg/day in the dog for 30 days or longer, there is replacement
of myocardial cells by proliferating fibroblasts and angioblasts, hemorrhage and
hemosiderin accumulation. These lesions can be produced by topical minoxidil
administration that gives systemic absorption of 0.5 to 1 mg/kg/day. Other
peripheral dilators, including an experimental agent, nicorandil, and theobromine,
have produced similar lesions.
(c) Epicarditis
A less fully studied lesion is focal epicarditis, seen in dogs after 2 days of oral
minoxidil. More recently, chronic proliferative epicarditis was observed in dogs
treated topically twice a day for 90 days. In a one year oral dog study,
serosanguinous pericardial fluid was seen.
(d) Hypertrophy and Dilation
Oral and topical studies in rats, dogs, monkeys (oral only), and rabbits (dermal
only) show cardiac hypertrophy and dilation. This is presumed to represent the
Reference ID: 3685475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
consequences of prolonged fluid overload; there is preliminary evidence in
monkeys that diuretics partly reverse these effects.
Autopsies of over 150 patients who died of various causes after receiving minoxidil for
hypertension have not revealed the characteristic hemorrhagic (especially atrial) lesions
seen in dogs and minipigs. While areas of papillary muscle and subendocardial necrosis
were occasionally seen, they occurred in the presence of known preexisting coronary
artery disease and were also seen in patients never exposed to minoxidil in another series
using similar, but not identical, autopsy methods.
INDICATIONS AND USAGE
Because of the potential for serious adverse effects, LONITEN Tablets are indicated only
in the treatment of hypertension that is symptomatic or associated with target organ
damage and is not manageable with maximum therapeutic doses of a diuretic plus two
other antihypertensive drugs. At the present time use in milder degrees of hypertension is
not recommended because the benefit-risk relationship in such patients has not been
defined.
LONITEN reduced supine diastolic blood pressure by 20 mm Hg or to 90 mm Hg or less
in approximately 75% of patients, most of who had hypertension that could not be
controlled by other drugs.
CONTRAINDICATIONS
LONITEN Tablets are contraindicated in pheochromocytoma, because it may stimulate
secretion of catecholamines from the tumor through its antihypertensive action.
LONITEN is contraindicated in those patients with a history of hypersensitivity to any of
the components of the preparation.
WARNINGS
1. Salt and Water Retention:
Congestive Heart Failure—concomitant use of an adequate diuretic is required—
LONITEN Tablets must usually be administered concomitantly with a diuretic adequate
to prevent fluid retention and possible congestive heart failure; a high ceiling (loop)
diuretic is almost always required. Body weight should be monitored closely. If
LONITEN is used without a diuretic, retention of several hundred milli-equivalents of
salt and corresponding volumes of water can occur within a few days, leading to
increased plasma and interstitial fluid volume and local or generalized edema. Diuretic
treatment alone, or in combination with restricted salt intake, will usually minimize fluid
retention, although reversible edema did develop in approximately 10% of nondialysis
patients so treated. Ascites has also been reported. Diuretic effectiveness was limited
mostly by disease-related impaired renal function. The condition of patients with pre
existing congestive heart failure occasionally deteriorated in association with fluid
retention although because of the fall in blood pressure (reduction of afterload), more
than twice as many improved than worsened. Rarely, refractory fluid retention may
require discontinuation of LONITEN. Provided that the patient is under close medical
supervision, it may be possible to resolve refractory salt retention by discontinuing
Reference ID: 3685475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
LONITEN for 1 or 2 days and then resuming treatment in conjunction with vigorous
diuretic therapy.
2. Concomitant Treatment to Prevent Tachycardia is Usually Required—
LONITEN increases the heart rate. Angina may worsen or appear for the first time during
LONITEN treatment, probably because of the increased oxygen demands associated with
increased heart rate and cardiac output. The increase in rate and the occurrence of angina
generally can be prevented by the concomitant administration of a beta-adrenergic
blocking drug or other sympathetic nervous system suppressant. The ability of beta
adrenergic blocking agents to minimize papillary muscle lesions in animals is further
reason to utilize such an agent concomitantly. Round-the-clock effectiveness of the
sympathetic suppressant should be ensured.
3. Pericarditis, Pericardial Effusion and Tamponade—There have been reports
of pericarditis occurring in association with the use of LONITEN. The relationship of this
association to renal status is uncertain. Pericardial effusion, occasionally with tamponade,
has been observed in about 3% of treated patients not on dialysis, especially those with
inadequate or compromised renal function. Although in many cases, the pericardial
effusion was associated with a connective tissue disease, the uremic syndrome,
congestive heart failure, or marked fluid retention, there have been instances in which
these potential causes of effusion were not present. Patients should be observed closely
for any suggestion of a pericardial disorder, and echocardiographic studies should be
carried out if suspicion arises. More vigorous diuretic therapy, dialysis,
pericardiocentesis, or surgery may be required. If the effusion persists, withdrawal of
LONITEN should be considered in light of other means of controlling the hypertension
and the patient’s clinical status.
4. Interaction with Guanethidine:
Although minoxidil does not itself cause orthostatic hypotension, its administration to
patients already receiving guanethidine can result in profound orthostatic effects. If at all
possible, guanethidine should be discontinued well before minoxidil is begun. Where this
is not possible, minoxidil therapy should be started in the hospital and the patient should
remain institutionalized until severe orthostatic effects are no longer present or the patient
has learned to avoid activities that provoke them.
5. Hazard of Rapid Control of Blood Pressure:
In patients with very severe blood pressure elevation, too rapid control of blood pressure,
especially with intravenous agents, can precipitate syncope, cerebrovascular accidents,
myocardial infarction and ischemia of special sense organs with resulting decrease or loss
of vision or hearing. Patients with compromised circulation or cryoglobulinemia may also
suffer ischemic episodes of the affected organs. Although such events have not been
unequivocally associated with minoxidil use, total experience is limited at present.
Any patient with malignant hypertension should have initial treatment with minoxidil
carried out in a hospital setting, both to assure that blood pressure is falling and to assure
that it is not falling more rapidly than intended.
Reference ID: 3685475
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
1. General Precautions
(a) Monitor fluid and electrolyte balance and body weight (see WARNINGS:
Salt and Water Retention).
(b) Observe patients for signs and symptoms of pericardial effusion (see
WARNINGS: Pericarditis, Pericardial Effusion, and Tamponade).
(c) Use after myocardial infarction—LONITEN Tablets have not been used in
patients who have had a myocardial infarction within the preceding month. It is
possible that a reduction of arterial pressure with LONITEN might further limit
blood flow to the myocardium, although this might be compensated by decreased
oxygen demand because of lower blood pressure.
(d) Hypersensitivity—Possible hypersensitivity to LONITEN, manifested as a skin
rash, has been seen in less than 1% of patients; whether the drug should be
discontinued when this occurs depends on treatment alternatives.
(e) Renal failure or dialysis—Patients may require smaller doses of LONITEN and
should have close medical supervision to prevent exacerbation of renal failure or
precipitation of cardiac failure.
2. Information for Patient
The patient should be fully aware of the importance of continuing all of his
antihypertensive medications and of the nature of symptoms that would suggest fluid
overload. A patient brochure has been prepared and is included with each LONITEN
package. The text of this brochure is reprinted at the end of the insert.
3. Laboratory Tests
Those laboratory tests which are abnormal at the time of initiation of minoxidil therapy,
such as urinalysis, renal function tests, EKG, chest x-ray, echocardiogram, etc., should be
repeated at intervals to ascertain whether improvement or deterioration is occurring under
minoxidil therapy. Initially such tests should be performed frequently, eg, 1–3 month
intervals; later as stabilization occurs, at intervals of 6–12 months.
4. Drug interactions
See "Interaction with Guanethidine" under WARNINGS.
5. Carcinogenesis, Mutagenesis and Impairment of Fertility—Two-year
carcinogenicity studies of minoxidil have been conducted by the dermal and oral (dietary)
routes of administration in mice and rats. There were no positive findings with the oral
(dietary) route of administration in rats.
In the two-year dermal study in mice, an increased incidence of mammary adenomas and
adenocarcinomas in the females at all dose levels (8, 25 and 80 mg/kg/day) was attributed
to increased prolactin activity. Hyperprolactinemia is a well-known mechanism in the
enhancement of mouse mammary tumors, but has not been associated with mammary
tumorigenesis in women. Additionally, topical minoxidil has not been shown to cause
hyperprolactinemia in women on clinical trials. Absorption of minoxidil through rodent
Reference ID: 3685475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
skin is greater than would be experienced by patients treated topically with minoxidil for
hair loss. Dietary administration of minoxidil to mice for up to 2 years was associated
with an increased incidence of malignant lymphomas in females at all dose levels (10, 25
and 63 mg/kg/day) and an increased incidence of hepatic nodules in males (63
mg/kg/day). There was no effect of dietary minoxidil on the incidence of malignant liver
tumors.
In the two-year dermal study in rats there were significant increases in incidence of
pheochromocytomas in males and females and preputial gland adenomas in males.
Changes in incidence of neoplasms found to be increased in the dermal or oral
carcinogenicity studies were typical of those expected in rodents treated with other
hypotensive agents (adrenal pheochromocytomas in rats), treatment-related hormonal
alterations (mammary carcinomas in female mice; preputial gland adenomas in male rats)
or representative of normal variations within the range of historical incidence for rodent
neoplasms (malignant lymphomas, liver nodules/adenomas in mice). Based on
differences in absorption of minoxidil and mechanisms of tumorigenesis in these rodent
species, none of these changes were considered to be relevant to the safety of patients
treated topically with minoxidil for hair loss.
There was no evidence of epithelial hyperplasia or tumorigenesis at the sites of topical
application of minoxidil in either species in the 2-year dermal carcinogenesis studies. No
evidence of carcinogenicity was detected in rats or rabbits treated topically with
minoxidil for one year. Topical minoxidil (2% and 5%) did not significantly (p<0.05)
reduce the latency period of UV light-initiated skin tumors in hairless mice, as compared
to controls, in a 12-month photocarcinogenicity study.
Minoxidil was not mutagenic in the Salmonella (Ames) test, the DNA damage alkaline
elution assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, the rat
bone marrow micronucleus assay, or the mouse bone marrow micronucleus assay. An
equivocal result was recorded in an in vitro cytogenetic assay using Chinese hamster cells
at long exposure times, but a similar assay using human lymphocytes was negative.
In a study in which male and female rats received one or five times the maximum
recommended human oral antihypertensive dose of minoxidil (multiples based on a 50 kg
patient) there was a dose-dependent reduction in conception rate.
6. Pregnancy
Teratogenic Effects
Pregnancy Category C. Oral administration of minoxidil has been associated with
evidence of increased fetal resorption in rabbits, but not rats, when administered at five
times the maximum recommended oral antihypertensive human dose. There was no
evidence of teratogenic effects in rats and rabbits. Subcutaneous administration of
minoxidil to pregnant rats at 80 mg/kg/day was maternally toxic but not teratogenic.
Higher subcutaneous doses produced evidence of developmental toxicity. There are no
adequate and well controlled studies in pregnant women. LONITEN should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Reference ID: 3685475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Neonatal hypertrichosis has been reported following exposure to minoxidil during
pregnancy.
7. Labor and Delivery
The effects on labor and delivery are unknown.
8. Nursing Mothers
There has been one report of minoxidil excretion in the breast milk of a woman treated
with 5 mg oral minoxidil twice daily for hypertension. Because of the potential for
adverse effects in nursing infants from minoxidil absorption, LONITEN should not be
administered to a nursing woman.
9. Pediatric Use
Use in pediatric patients has been limited to date, particularly in infants. The
recommendations under DOSAGE AND ADMINISTRATION can be considered only a
rough guide at present and a careful titration is essential.
10. Geriatric Use
Clinical studies of LONITEN Tablets did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the
elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
11. Unapproved Use
Use of LONITEN Tablets, in any formulation, to promote hair growth is not an approved
indication. While clinical trials with ROGAINE® Topical Solution 2% demonstrated that
formulation and dosage were safe and effective, the effects of extemporaneous
formulations and dosages have not been shown to be safe or effective. Because systemic
absorption of topically applied drug may occur and is dependent on vehicle and/or
method of use, extemporaneous topical formulations made from LONITEN should be
considered to share in the full range of CONTRAINDICATIONS, WARNINGS,
PRECAUTIONS, and ADVERSE REACTIONS listed in this insert. In addition, skin
intolerance to drug and/or vehicle may occur.
ADVERSE REACTIONS
1. Salt and Water Retention (see WARNINGS: Concomitant Use of Adequate
Diuretic is Required)—Temporary edema developed in 7% of patients who were not
edematous at the start of therapy.
2. Pericarditis, Pericardial Effusion and Tamponade (see WARNINGS).
3. Dermatologic—Hypertrichosis—Elongation, thickening, and enhanced pigmentation
of fine body hair are seen in about 80% of patients taking LONITEN Tablets. This
Reference ID: 3685475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
develops within 3 to 6 weeks after starting therapy. It is usually first noticed on the
temples, between the eyebrows, between the hairline and the eyebrows, or in the side-
burn area of the upper lateral cheek, later extending to the back, arms, legs, and scalp.
Upon discontinuation of LONITEN, new hair growth stops, but 1 to 6 months may be
required for restoration to pretreatment appearance. No endocrine abnormalities have
been found to explain the abnormal hair growth; thus, it is hypertrichosis without
virilism. Hair growth is especially disturbing to children and women and such patients
should be thoroughly informed about this effect before therapy with LONITEN is begun.
Allergic—Rashes have been reported, including rare reports of bullous eruptions, toxic
epidermal necrolysis, and Stevens-Johnson Syndrome.
4. Hematologic—Thrombocytopenia and leukopenia (WBC<3000/mm3) have rarely
been reported.
5. Gastrointestinal—Nausea and/or vomiting has been reported. In clinical trials the
incidence of nausea and vomiting associated with the underlying disease has shown a
decrease from pretrial levels.
6. Miscellaneous—Breast tenderness—This developed in less than 1% of patients.
7. Altered Laboratory Findings — (a) ECG changes—Changes in direction and
magnitude of the ECG T-waves occur in approximately 60% of patients treated with
LONITEN. In rare instances a large negative amplitude of the T-wave may encroach
upon the S-T segment, but the S-T segment is not independently altered. These changes
usually disappear with continuance of treatment and revert to the pretreatment state if
LONITEN is discontinued. No symptoms have been associated with these changes, nor
have there been alterations in blood cell counts or in plasma enzyme concentrations that
would suggest myocardial damage. Long-term treatment of patients manifesting such
changes has provided no evidence of deteriorating cardiac function. At present the
changes appear to be nonspecific and without identifiable clinical significance. (b)
Effects of hemodilution—hematocrit, hemoglobin and erythrocyte count usually fall
about 7% initially and then recover to pretreatment levels. (c) Other—Alkaline
phosphatase increased varyingly without other evidence of liver or bone abnormality.
Serum creatinine increased an average of 6% and BUN slightly more, but later declined
to pretreatment levels.
OVERDOSAGE
There have been only a few instances of deliberate or accidental overdosage with
LONITEN Tablets. One patient recovered after taking 50 mg of minoxidil together with
500 mg of a barbiturate. When exaggerated hypotension is encountered, it is most likely
to occur in association with residual sympathetic nervous system blockade from previous
therapy (guanethidine-like effects or alpha-adrenergic blockage), which prevents the
usual compensatory maintenance of blood pressure. Intravenous administration of normal
saline will help to maintain blood pressure and facilitate urine formation in these patients.
Sympathomimetic drugs such as norepinephrine or epinephrine should be avoided
Reference ID: 3685475
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because of their excessive cardiac stimulating action. Phenylephrine, angiotensin II,
vasopressin, and dopamine all reverse hypotension due to LONITEN, but should only be
used if underperfusion of a vital organ is evident.
Radioimmunoassay can be performed to determine the concentration of minoxidil in the
blood. At the maximum adult dose of 100 mg/day, peak blood levels of 1641 ng/mL and
2441 ng/mL were observed in two patients, respectively. Due to patient-to-patient
variation in blood levels, it is difficult to establish an overdosage warning level. In
general, a substantial increase above 2000 ng/mL should be regarded as overdosage,
unless the physician is aware that the patient has taken no more than the maximum dose.
Oral LD50 in rats has ranged from 1321 – 3492 mg/kg; in mice, 2456 – 2648 mg/kg.
DOSAGE AND ADMINISTRATION
Patients over 12 years of age: The recommended initial dosage of LONITEN
Tablets is 5 mg of minoxidil given as a single daily dose. Daily dosage can be increased
to 10, 20 and then to 40 mg in single or divided doses if required for optimum blood
pressure control. The effective dosage range is usually 10 to 40 mg per day. The
maximum recommended dosage is 100 mg per day.
Patients under 12 years of age: The initial dosage is 0.2 mg/kg minoxidil as a single
daily dose. The dosage may be increased in 50 to 100% increments until optimum blood
pressure control is achieved. The effective dosage range is usually 0.25 to 1.0 mg/kg/day.
The maximum recommended dosage is 50 mg daily (see 9. Pediatric Use under
PRECAUTIONS).
Dose frequency: The magnitude of within-day fluctuation of arterial pressure during
therapy with LONITEN is directly proportional to the extent of pressure reduction. If
supine diastolic pressure has been reduced less than 30 mm Hg, the drug need be
administered only once a day; if supine diastolic pressure has been reduced more than 30
mm Hg, the daily dosage should be divided into two equal parts.
Frequency of dosage adjustment: Dosage must be titrated carefully according to
individual response. Intervals between dosage adjustments normally should be at least 3
days since the full response to a given dose is not obtained for at least that amount of
time. Where a more rapid management of hypertension is required, dose
adjustments can be made every 6 hours if the patient is carefully monitored.
Concomitant therapy: Diuretic and beta-blocker or other sympathetic nervous system
suppressant.
Diuretics: LONITEN must be used in conjunction with a diuretic in patients relying on
renal function for maintaining salt and water balance. Diuretics have been used at the
following dosages when starting therapy with LONITEN: hydrochlorothiazide (50 mg,
b.i.d.) or other thiazides at equieffective dosage; chlorthalidone (50 to 100 mg, once
daily); furosemide (40 mg, b.i.d.). If excessive salt and water retention results in a weight
Reference ID: 3685475
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gain of more than 5 pounds, diuretic therapy should be changed to furosemide; if the
patient is already taking furosemide, dosage should be increased in accordance with the
patient’s requirements.
Beta-blocker or other sympathetic nervous system suppressants: When
therapy with LONITEN is begun, the dosage of a beta-adrenergic receptor blocking drug
should be the equivalent of 80 to 160 mg of propranolol per day in divided doses.
If beta-blockers are contraindicated, methyldopa (250 to 750 mg, b.i.d.) may be used
instead. Methyldopa must be given for at least 24 hours before starting therapy with
LONITEN because of the delay in the onset of methyldopa’s action. Limited clinical
experience indicates that clonidine may also be used to prevent tachycardia induced by
LONITEN; the usual dosage is 0.1 to 0.2 mg twice daily.
Sympathetic nervous system suppressants may not completely prevent an increase in
heart rate due to LONITEN but usually do prevent tachycardia. Typically, patients
receiving a beta-blocker prior to initiation of therapy with LONITEN have a bradycardia
and can be expected to have an increase in heart rate toward normal when LONITEN is
added. When treatment with LONITEN and beta-blocker or other sympathetic nervous
system suppressant are begun simultaneously, their opposing cardiac effects usually
nullify each other, leading to little change in heart rate.
HOW SUPPLIED
LONITEN Tablets are available as follows:
2.5 mg (white, round, scored, imprinted U/121 and 2½)
Bottles of 100
NDC 0009-0121-01
10 mg (white, round, scored, imprinted LONITEN 10)
Bottles of 100
NDC 0009-0137-01
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. company logo
LAB-0168-0.x
Revised January 2015
Reference ID: 3685475
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PATIENT INFORMATION
LONITEN Tablets contain minoxidil, a medicine for the treatment of high blood pressure
in the patient who has not been controlled or is experiencing unacceptable side effects
with other medications. It must usually be taken with other medicines.
Be absolutely sure to take all of your medicines for high blood pressure according to your
doctor’s instructions. Do not stop taking LONITEN unless your doctor tells you to. Do
not give any of your medicine to other people.
It is important that you look for the warning signals of certain undesired effects of
LONITEN. Call your doctor if they occur. Your doctor will need to see you regularly
while you are taking LONITEN. Be sure to keep all your appointments or to arrange for
new ones if you must miss one.
Do not hesitate to call your doctor if any discomforts or problems occur.
The information here is intended to help you take LONITEN properly. It does not tell you
all there is to know about LONITEN. There is a more technical leaflet that you may
request from the pharmacist; you may need your doctor’s help in understanding parts of
that leaflet.
What is LONITEN?
LONITEN Tablets contain minoxidil which is a drug for lowering the blood pressure. It
works by relaxing and enlarging certain small blood vessels so that blood flows through
them more easily. usage illustration
Why lower blood pressure?
Your doctor has prescribed LONITEN to lower your blood pressure and protect vital
parts of your body. Uncontrolled blood pressure can cause stroke, heart failure, blindness,
kidney failure, and heart attacks. usage illustration
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Most people with high blood pressure need to take medicines to treat it for their whole
lives.
Who should take LONITEN?
There are many people with high blood pressure, but most of them do not need
LONITEN. LONITEN is used ONLY when your doctor decides that:
1. your high blood pressure is severe;
2. your high blood pressure is causing symptoms or damage to vital organs; and
3. other medicines did not work well enough or had very disturbing side effects. usage illustration
LONITEN should be taken only when a doctor prescribes it. Never give any of your
LONITEN Tablets, or any other high blood pressure medicine, to a friend or relative.
Pregnancy: In some cases doctors may prescribe LONITEN for women who are
pregnant or who are planning to have children. However, its safe use in pregnancy has
not been established. Laboratory animals had a reduced ability to become pregnant and a
reduced survival of offspring while taking LONITEN. If you are pregnant or are planning
to become pregnant, be sure to tell your doctor.
How to take LONITEN.
Usually, your doctor will prescribe two other medicines along with LONITEN. These
will help lower blood pressure and will help prevent undesired effects of LONITEN.
Often, when a medicine like LONITEN lowers blood pressure, your body tries to return
the blood pressure to the original higher level. It does this by holding on to water and salt
(so there will be more fluid to pump) and by making your heart beat faster. To prevent
this, your doctor will usually prescribe a water tablet to remove the extra salt and water
usage illustration
Reference ID: 3685475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
You must follow your doctor’s instructions exactly, taking all the prescribed
medicines, in the right amounts, each day. These medicines will help keep your blood
pressure down. The water tablet and heart beat medicine will help prevent the undesired
effects of LONITEN.
LONITEN Tablets come in two strengths (2½ milligrams and 10 milligrams) that are
marked on each tablet. Pay close attention to the tablet markings to be sure you are taking
the correct strength. Your doctor may prescribe half a tablet; the tablets are scored (partly
cut on one side) so that you can easily break them. usage illustration
When you first start taking LONITEN, your doctor may need to see you often in order to
adjust your dosage. Take all your medicine according to the schedule prescribed by your
doctor. Do not skip any doses. If you should forget a dose of LONITEN, wait until it
is time for your next dose, then continue with your regular schedule. Remember: do
not stop taking LONITEN, or any of your other high blood pressure medicines,
without checking with your doctor. Make sure that any doctor treating or examining
you knows that you are taking high blood pressure medicines, including LONITEN.
WARNING SIGNALS
Even if you take all your medicines correctly, LONITEN Tablets may cause undesired
effects. Some of these are serious and you should be on the lookout for them. If any of
the following warning signals occur, you must call your doctor immediately:
1. Increase in heart rate—You should measure your heart rate by counting your pulse
rate while you are resting. If you have an increase of 20 beats or more a minute over
your normal pulse, contact your doctor immediately. If you do not know how to take your
pulse rate, ask your doctor. Also ask your doctor how often to check your pulse. usage illustration
2. Rapid weight gain of more than 5 pounds—You should weigh yourself daily. If you
quickly gain five or more pounds, or if there is any swelling or puffiness in the face,
hands, ankles, or stomach area, this could be a sign that you are retaining body fluids.
Your doctor may have to change your drugs or change the dose of your drugs. You may
also need to reduce the amount of salt you eat. A smaller weight gain (2 to 3 pounds)
Reference ID: 3685475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
often occurs when treatment is started. You may lose this extra weight with continued
treatment. usage illustration
3. Increased difficulty in breathing, especially when lying down. This too may be due
to an increase of body fluids. I t can also happen because your high blood pressure is
getting worse. In either case, you might require treatment with other medicines. usage illustration
4. New or worsening of pain in the chest, arm, or shoulder or signs of severe
indigestion—These could be signs of serious heart problems. usage illustration
5. Dizziness, lightheadedness or fainting—These can be signs of high blood pressure or
they may be side effects from one of the medicines. Your doctor may need to change or
adjust the dosage of the medicines you are taking. usage illustration
Reference ID: 3685475
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For current labeling information, please visit https://www.fda.gov/drugsatfda
OTHER UNDESIRED EFFECTS
LONITEN Tablets can cause other undesired effects such as nausea and/or vomiting that
are annoying but not dangerous. Do not stop taking the drug because of these other
undesired effects without talking to your doctor.
Hair growth: About 8 out of every 10 patients who have taken LONITEN noticed that
fine body hair grew darker or longer on certain parts of the body. This happened about
3 to 6 weeks after beginning treatment. The hair may first be noticed on the forehead and
temples, between the eyebrows, or on the upper part of the cheeks. Later, hair may grow
on the back, arms, legs, or scalp. Although hair growth may not be noticeable to some
patients, it often is bothersome in women and children. Unwanted hair can be
controlled with a hair remover or by shaving. The extra hair is not permanent, it
disappears within 1 to 6 months of stopping LONITEN. Nevertheless, you should not
stop taking LONITEN without first talking to your doctor.
A few patients have developed a rash or breast tenderness while taking LONITEN
Tablets, but this is unusual. company logo
LAB-0169-0.x
Revised January 2015
Reference ID: 3685475
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|
custom-source
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2025-02-12T13:44:38.167778
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018154s026lbl.pdf', 'application_number': 18154, 'submission_type': 'SUPPL ', 'submission_number': 26}
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11,174
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NDA 18163 FDA Approved Labeling text 11.4.10
Restoril™
(temazepam)
Capsules USP company logo
Rx only
DESCRIPTION
Restoril™ (temazepam) is a benzodiazepine hypnotic agent. The chemical name is 7-chloro
1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, and the structural
formula is: structural formula
C16H13ClN2O2
MW = 300.74
Temazepam is a white, crystalline substance, very slightly soluble in water and sparingly soluble
in alcohol USP.
Restoril™ (temazepam) capsules USP, 7.5 mg, 15 mg, 22.5 mg, and 30 mg, are for oral
administration.
7.5 mg, 15 mg, 22.5 mg, and 30 mg Capsules
Active Ingredient: temazepam USP
7.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, iron oxide red, shellac, shellac glaze, SD-35A alcohol.
15 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
Reference ID: 2859677
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NDA 18163 FDA Approved Labeling text 11.4.10
22.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
30 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
CLINICAL PHARMACOLOGY
Pharmacokinetics
In a single and multiple dose absorption, distribution, metabolism, and excretion (ADME) study,
using 3H labeled drug, Restoril was well absorbed and found to have minimal (8%) first pass
metabolism. There were no active metabolites formed and the only significant metabolite present
in blood was the O-conjugate. The unchanged drug was 96% bound to plasma proteins. The
blood level decline of the parent drug was biphasic with the short half-life ranging from 0.4 to
0.6 hours and the terminal half-life from 3.5 to 18.4 hours (mean 8.8 hours), depending on the
study population and method of determination. Metabolites were formed with a half-life of
10 hours and excreted with a half-life of approximately 2 hours. Thus, formation of the major
metabolite is the rate limiting step in the biodisposition of temazepam. There is no accumulation
of metabolites. A dose-proportional relationship has been established for the area under the
plasma concentration/time curve over the 15 to 30 mg dose range.
Temazepam was completely metabolized through conjugation prior to excretion; 80% to 90% of
the dose appeared in the urine. The major metabolite was the O-conjugate of temazepam (90%);
the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).
Bioavailability, Induction, and Plasma Levels
Following ingestion of a 30 mg Restoril capsule, measurable plasma concentrations were
achieved 10 to 20 minutes after dosing with peak plasma levels ranging from 666 to 982 ng/mL
(mean 865 ng/mL) occurring approximately 1.2 to 1.6 hours (mean 1.5 hours) after dosing.
In a 7 day study, in which subjects were given a 30 mg Restoril capsule 1 hour before retiring,
steady-state (as measured by the attainment of maximal trough concentrations) was achieved by
the third dose. Mean plasma levels of temazepam (for days 2 to 7) were 260±210 ng/mL at
9 hours and 75±80 ng/mL at 24 hours after dosing. A slight trend toward declining 24 hour
Reference ID: 2859677
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NDA 18163 FDA Approved Labeling text 11.4.10
plasma levels was seen after day 4 in the study, however, the 24 hour plasma levels were quite
variable.
At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man.
Elimination Rate of Benzodiazepine Hypnotics and Profile of Common Untoward
Effects
The type and duration of hypnotic effects and the profile of unwanted effects during
administration of benzodiazepine hypnotics may be influenced by the biologic half-life of the
administered drug and for some hypnotics, the half-life of any active metabolites formed.
Benzodiazepine hypnotics have a spectrum of half-lives from short (<4 hours) to long
(>20 hours). When half-lives are long, drug (and for some drugs their active metabolites) may
accumulate during periods of nightly administration and be associated with impairments of
cognitive and/or motor performance during waking hours; the possibility of interaction with
other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are shorter, drug
(and, where appropriate, its active metabolites) will be cleared before the next dose is ingested,
and carry-over effects related to excessive sedation or CNS depression should be minimal or
absent. However, during nightly use for an extended period, pharmacodynamic tolerance or
adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a short
elimination half-life, it is possible that a relative deficiency of the drug, or, if appropriate, its
active metabolites (i.e., in relationship to the receptor site) may occur at some point in the
interval between each night’s use. This sequence of events may account for 2 clinical findings
reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine
hypnotics, namely, increased wakefulness during the last third of the night, and the appearance
of increased signs of daytime anxiety.
Controlled Trials Supporting Efficacy
Restoril improved sleep parameters in clinical studies. Residual medication effects (“hangover”)
were essentially absent. Early morning awakening, a particular problem in the geriatric patient,
was significantly reduced.
Patients with chronic insomnia were evaluated in 2 week, placebo controlled sleep laboratory
studies with Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime.
There was a linear dose-response improvement in total sleep time and sleep latency, with
significant drug-placebo differences at 2 weeks occurring only for total sleep time at the 2 higher
doses, and for sleep latency only at the highest dose.
In these sleep laboratory studies, REM sleep was essentially unchanged and slow wave sleep was
decreased. No measurable effects on daytime alertness or performance occurred following
Restoril treatment or during the withdrawal period, even though a transient sleep disturbance in
some sleep parameters was observed following withdrawal of the higher doses. There was no
evidence of tolerance development in the sleep laboratory parameters when patients were given
Restoril nightly for at least 2 weeks.
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NDA 18163 FDA Approved Labeling text 11.4.10
In addition, normal subjects with transient insomnia associated with first night adaptation to the
sleep laboratory were evaluated in 24 hour, placebo controlled sleep laboratory studies with
Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. There was a
linear dose-response improvement in total sleep time, sleep latency and number of awakenings,
with significant drug-placebo differences occurring for sleep latency at all doses, for total sleep
time at the 2 higher doses and for number of awakenings only at the 30 mg dose.
INDICATIONS AND USAGE
Restoril™ (temazepam) is indicated for the short-term treatment of insomnia (generally 7 to 10
days).
For patients with short-term insomnia, instructions in the prescription should indicate that
Restoril™ (temazepam) should be used for short periods of time (7 to 10 days).
The clinical trials performed in support of efficacy were 2 weeks in duration with the final
formal assessment of sleep latency performed at the end of treatment.
CONTRAINDICATIONS
Benzodiazepines may cause fetal harm when administered to a pregnant woman. An increased
risk of congenital malformations associated with the use of diazepam and chlordiazepoxide
during the first trimester of pregnancy has been suggested in several studies. Transplacental
distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses
of a benzodiazepine hypnotic during the last weeks of pregnancy.
Reproduction studies in animals with temazepam were performed in rats and rabbits. In a
perinatal-postnatal study in rats, oral doses of 60 mg/kg/day resulted in increasing nursling
mortality. Teratology studies in rats demonstrated increased fetal resorptions at doses of 30 and
120 mg/kg in one study and increased occurrence of rudimentary ribs, which are considered
skeletal variants, in a second study at doses of 240 mg/kg or higher. In rabbits, occasional
abnormalities such as exencephaly and fusion or asymmetry of ribs were reported without dose
relationship. Although these abnormalities were not found in the concurrent control group, they
have been reported to occur randomly in historical controls. At doses of 40 mg/kg or higher,
there was an increased incidence of the 13th rib variant when compared to the incidence in
concurrent and historical controls.
Restoril is contraindicated in women who are or may become pregnant. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to the fetus. Patients should be instructed to discontinue the drug
prior to becoming pregnant. The possibility that a woman of childbearing potential may be
pregnant at the time of institution of therapy should be considered.
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NDA 18163 FDA Approved Labeling text 11.4.10
WARNINGS
Sleep disturbance may be the presenting manifestation of an underlying physical and/or
psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia
should only be made after the patient has been carefully evaluated. The failure of insomnia to
remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric
and/or medical illness that should be evaluated. Worsening of insomnia may be the
consequence of an unrecognized psychiatric or physical disorder as may the emergence of new
abnormalities of thinking or behavior. Such abnormalities have also been reported to occur in
association with the use of drugs with central nervous system depressant activity, including those
of the benzodiazepine class. Because some of the worrisome adverse effects of benzodiazepines,
including Restoril, appear to be dose related (see PRECAUTIONS and DOSAGE AND
ADMINISTRATION), it is important to use the lowest possible effective dose. Elderly patients
are especially at risk.
Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and
extroversion that seem out of character, similar to that seen with alcohol. Other kinds of
behavioral changes can also occur, for example, bizarre behavior, agitation, hallucinations, and
depersonalization. Complex behaviors such as “sleep-driving” (i.e., driving while not fully
awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported.
These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced
persons. Although behaviors such as sleep-driving may occur with Restoril alone at therapeutic
doses, the use of alcohol and other CNS depressants with Restoril appears to increase the risk of
such behaviors, as does the use of Restoril at doses exceeding the maximum recommended dose.
Due to the risk to the patient and the community, discontinuation of Restoril should be strongly
considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g.,
preparing and eating food, making phone calls, or having sex) have been reported in patients
who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually
do not remember these events. Amnesia and other neuro-psychiatric symptoms may occur
unpredictably. In primarily depressed patients, worsening of depression, including suicidal
thinking has been reported in association with the use of sedative/hypnotics.
It can rarely be determined with certainty whether a particular instance of the abnormal
behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying
psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or
symptom of concern requires careful and immediate evaluation.
Withdrawal symptoms (of the barbiturate type) have occurred after the abrupt discontinuation of
benzodiazepines (see DRUG ABUSE AND DEPENDENCE).
Severe Anaphylactic and Anaphylactoid Reactions
Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients
after taking the first or subsequent doses of sedative-hypnotics, including Restoril. Some patients
have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that
suggest anaphylaxis. Some patients have required medical therapy in the emergency department.
If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.
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NDA 18163 FDA Approved Labeling text 11.4.10
Patients who develop angioedema after treatment with Restoril should not be rechallenged with
the drug.
PRECAUTIONS
General
Since the risk of the development of oversedation, dizziness, confusion, and/or ataxia increases
substantially with larger doses of benzodiazepines in elderly and debilitated patients, 7.5 mg of
Restoril is recommended as the initial dosage for such patients.
Restoril should be administered with caution in severely depressed patients or those in whom
there is any evidence of latent depression; it should be recognized that suicidal tendencies may
be present and protective measures may be necessary.
The usual precautions should be observed in patients with impaired renal or hepatic function and
in patients with chronic pulmonary insufficiency.
If Restoril is to be combined with other drugs having known hypnotic properties or CNS-
depressant effects, consideration should be given to potential additive effects.
The possibility of a synergistic effect exists with the co-administration of Restoril and
diphenhydramine. One case of stillbirth at term has been reported 8 hours after a pregnant patient
received Restoril and diphenhydramine. A cause and effect relationship has not yet been
determined (see CONTRAINDICATIONS).
Information for Patients
The text of a patient Medication Guide is printed at the end of this insert. To assure safe and
effective use of Restoril, the information and instructions provided in this patient Medication
Guide should be discussed with patients.
Special Concerns
“Sleep-Driving” and Other Complex Behaviors – There have been reports of people getting
out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often
with no memory of the event. If a patient experiences such an episode, it should be reported to
his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more
likely to occur when Restoril is taken with alcohol or other central nervous system depressants
(see WARNINGS). Other complex behaviors (e.g., preparing and eating food, making phone
calls, or having sex) have been reported in patients who are not fully awake after taking a
sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
Laboratory Tests
The usual precautions should be observed in patients with impaired renal or hepatic function and
in patients with chronic pulmonary insufficiency. Abnormal liver function tests as well as blood
dyscrasias have been reported with benzodiazepines.
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NDA 18163 FDA Approved Labeling text 11.4.10
Drug Interactions
The pharmacokinetic profile of temazepam does not appear to be altered by orally administered
cimetidine dosed according to labeling.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in rats at dietary temazepam doses up to 160 mg/kg/day
for 24 months and in mice at dietary doses of 160 mg/kg/day for 18 months. No evidence of
carcinogenicity was observed although hyperplastic liver nodules were observed in female mice
exposed to the highest dose. The clinical significance of this finding is not known.
Fertility in male and female rats was not adversely affected by Restoril.
No mutagenicity tests have been done with temazepam.
Pregnancy
Pregnancy Category X (see CONTRAINDICATIONS).
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Restoril is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Restoril did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in response between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy commonly observed in this
population. Restoril 7.5 mg is recommended as the initial dosage for patients aged 65 and over
since the risk of the development of oversedation, dizziness, confusion, ataxia and/or falls
increases substantially with larger doses of benzodiazepines in elderly and debilitated patients.
ADVERSE REACTIONS
During controlled clinical studies in which 1076 patients received Restoril at bedtime, the drug
was well tolerated. Side effects were usually mild and transient. Adverse reactions occurring in
1% or more of patients are presented in the following table:
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NDA 18163 FDA Approved Labeling text 11.4.10
Drowsiness
9.1
5.6
Headache
8.5
9.1
Fatigue
4.8
4.7
Nervousness
4.6
8.2
Lethargy
4.5
3.4
Dizziness
4.5
3.3
Nausea
3.1
3.8
Hangover
2.5
1.1
Anxiety
2.0
1.5
Depression
1.7
1.8
Dry Mouth
1.7
2.2
Diarrhea
1.7
1.1
Abdominal Discomfort
1.5
1.9
Euphoria
1.5
0.4
Weakness
1.4
0.9
Confusion
1.3
0.5
Blurred Vision
1.3
1.3
Nightmares
1.2
1.7
Vertigo
1.2
0.8
The following adverse events have been reported less frequently (0.5% to 0.9%):
Central Nervous System – anorexia, ataxia, equilibrium loss, tremor, increased dreaming
Cardiovascular – dyspnea, palpitations
Gastrointestinal – vomiting
Musculoskeletal – backache
Special Senses – hyperhidrosis, burning eyes
Amnesia, hallucinations, horizontal nystagmus, and paradoxical reactions including restlessness,
overstimulation and agitation were rare (less than 0.5%).
DRUG ABUSE AND DEPENDENCE
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is
characterized by misuse of the drug for non-medical purposes, often in combination with other
psychoactive substances. Physical dependence is a state of adaptation that is manifested by a
specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction,
decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of
adaptation in which exposure to a drug induces changes that result in a diminution of one or
more of the drug’s effects over time. Tolerance may occur to both the desired and undesired
effects of drugs and may develop at different rates for different effects.
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Restoril
Placebo
% Incidence
% Incidence
(n=1076)
(n=783)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18163 FDA Approved Labeling text 11.4.10
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use, compulsive
use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a
multidisciplinary approach, but relapse is common.
Controlled Substance
Restoril is a controlled substance in Schedule IV.
Abuse and Dependence
Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol
(convulsions, tremor, abdominal, and muscle cramps, vomiting, and sweating), have occurred
following abrupt discontinuance of benzodiazepines. The more severe withdrawal symptoms
have usually been limited to those patients who received excessive doses over an extended
period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been
reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic
levels for several months. Consequently, after extended therapy at doses higher than 15 mg,
abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule
followed. As with any hypnotic, caution must be exercised in administering Restoril to
individuals known to be addiction-prone or to those whose history suggests they may increase
the dosage on their own initiative. It is desirable to limit repeated prescriptions without adequate
medical supervision.
OVERDOSAGE
Manifestations of acute overdosage of Restoril can be expected to reflect the CNS effects of the
drug and include somnolence, confusion, and coma, with reduced or absent reflexes, respiratory
depression, and hypotension. The oral LD50 of Restoril was 1963 mg/kg in mice, 1833 mg/kg in
rats, and >2400 mg/kg in rabbits.
Treatment
If the patient is conscious, vomiting should be induced mechanically or with emetics. Gastric
lavage should be employed utilizing concurrently a cuffed endotracheal tube if the patient is
unconscious to prevent aspiration and pulmonary complications. Maintenance of adequate
pulmonary ventilation is essential. The use of pressor agents intravenously may be necessary to
combat hypotension. Fluids should be administered intravenously to encourage diuresis. The
value of dialysis has not been determined. If excitation occurs, barbiturates should not be used. It
should be borne in mind that multiple agents may have been ingested. Flumazenil
(Romazicon®)*, a specific benzodiazepine receptor antagonist, is indicated for the complete or
partial reversal of the sedative effects of benzodiazepines and may be used in situations when an
overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil,
necessary measures should be instituted to secure airway, ventilation, and intravenous access.
Flumazenil is intended as an adjunct to, not as a substitute for, proper management of
benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation,
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NDA 18163 FDA Approved Labeling text 11.4.10
respiratory depression, and other residual benzodiazepine effects for an appropriate period after
treatment. The prescriber should be aware of a risk of seizure in association with flumazenil
treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant
overdose. The complete flumazenil package insert including CONTRAINDICATIONS,
WARNINGS, and PRECAUTIONS should be consulted prior to use.
Up-to-date information about the treatment of overdose can often be obtained from a certified
Regional Poison Control Center. Telephone numbers of certified Regional Poison Control
Centers are listed in the Physicians’ Desk Reference®**.
DOSAGE AND ADMINISTRATION
While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for
some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be
sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that
therapy be initiated with 7.5 mg until individual responses are determined.
HOW SUPPLIED
Restoril™ (temazepam) Capsules USP
7.5 mg
Blue and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and M® on the
other side in red, and a blue cap imprinted “RESTORIL 7.5 mg” twice in red.
Bottle of 30 ...................NDC 0406-9915-03
Bottle of 100 .................NDC 0406-9915-01
15 mg
Maroon and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and M® on
the other side in red, and a maroon cap imprinted “RESTORIL 15 mg” twice in white.
Bottle of 100 . . . . . . . . .NDC 0406-9916-01
22.5 mg
Opaque blue capsules, with the opaque blue body imprinted “FOR SLEEP” on one side and M®
on the other side in red, and an opaque blue cap imprinted “RESTORIL 22.5 mg” twice in red.
Bottle of 30 . . . . . . . . . .NDC 0406-9914-03
30 mg
Maroon and blue capsules, with the blue body imprinted “FOR SLEEP” on one side and M® on
the other side in red, and a maroon cap imprinted “RESTORIL 30 mg” twice in white.
Bottle of 100 . . . . . . . . .NDC 0406-9917-01
Dispense in a well-closed, light-resistant container with a child-resistant closure.
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NDA 18163 FDA Approved Labeling text 11.4.10
Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
M and Restoril are trademarks of Mallinckrodt Inc.
*Romazicon is the registered trademark of Hoffman-LaRoche Inc.
**Trademark of Medical Economics Company, Inc.
Mallinckrodt Inc.
Hazelwood, MO 63042 U.S.A.
Rev 11/2010
MEDICATION GUIDE
RESTORIL™ (res-tə-ril) Capsules
C-IV
(temazepam)
Read the Medication Guide that comes with RESTORIL before you start taking it and each time
you get a refill. There may be new information. This Medication Guide does not take the place
of talking to your doctor about your medical condition or treatment.
What is the most important information I should know about RESTORIL?
After taking RESTORIL, you may get up out of bed while not being fully awake and do an
activity that you do not know you are doing. The next morning, you may not remember
that you did anything during the night. You have a higher chance for doing these activities if
you drink alcohol or take other medicines that make you sleepy with RESTORIL. Reported
activities include:
• driving a car (“sleep-driving”)
• making and eating food
• talking on the phone
• having sex
• sleep-walking
Call your doctor right away if you find out that you have done any of the above activities
after taking RESTORIL.
Important:
1. Take RESTORIL exactly as prescribed
• Do not take more RESTORIL than prescribed.
• Take RESTORIL right before you get in bed, not sooner.
2. Do not take RESTORIL if you:
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NDA 18163 FDA Approved Labeling text 11.4.10
• drink alcohol
• take other medicines that can make you sleepy. Talk to your doctor about all of your
medicines. Your doctor will tell you if you can take RESTORIL with your other medicines.
• cannot get a full night’s sleep.
What is RESTORIL?
RESTORIL is a sedative-hypnotic (sleep) medicine. RESTORIL is used in adults for the short-
term (usually 7 to 10 days) treatment of a sleep problem called insomnia. Symptoms of
insomnia include:
• trouble falling asleep
• waking up often during the night
RESTORIL is not for children.
RESTORIL is a federally controlled substance (C-IV) because it can be abused or lead to
dependence. Keep RESTORIL in a safe place to prevent misuse and abuse. Selling or giving
away RESTORIL may harm others, and is against the law. Tell your doctor if you have ever
abused or been dependent on alcohol, prescription medicines or street drugs.
Who should not take RESTORIL?
Do not take RESTORIL if you are pregnant or planning to become pregnant. RESTORIL
may cause birth defects or harm a fetus (unborn baby).
RESTORIL may not be right for you. Before starting RESTORIL, tell your doctor about
all of your health conditions, including if you:
• have a history of depression, mental illness, or suicidal thoughts
• have a history of drug or alcohol abuse or addiction
• have kidney or liver disease
• have a lung disease or breathing problems
• are breastfeeding
Tell your doctor about all of the medicines you take including prescription and nonprescription
medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes
causing serious side effects. Do not take RESTORIL with other medicines that can make
you sleepy.
Know the medicines you take. Keep a list of your medicines with you to show your doctor and
pharmacist each time you get a new medicine.
How should I take RESTORIL?
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NDA 18163 FDA Approved Labeling text 11.4.10
• Take RESTORIL exactly as prescribed. Do not take more RESTORIL than prescribed for
you.
• Take RESTORIL right before you get into bed.
• Do not take RESTORIL unless you are able to get a full night’s sleep before you must
be active again.
• Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may
mean that there is another condition causing your sleep problems.
• If you take too much RESTORIL or overdose, call your doctor or poison control center right
away, or get emergency treatment.
What are the possible side effects of RESTORIL?
Possible serious side effects of RESTORIL include:
• getting out of bed while not being fully awake and do an activity that you do not know
you are doing.
(See “What is the most important information I should know about
RESTORIL?”)
• abnormal thoughts and behavior. Symptoms include more outgoing or aggressive
behavior than normal, confusion, agitation, hallucinations, worsening of depression, and
suicidal thoughts.
• memory loss
• anxiety
• severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble
breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms
after taking RESTORIL.
Call your doctor right away if you have any of the above side effects or any other side
effects that worry you while using RESTORIL.
The most common side effects of RESTORIL are:
• drowsiness
• headache
• tiredness
• nervousness
• dizziness
• nausea
• “hangover” feeling the day after taking RESTORIL
• You may still feel drowsy the next day after taking RESTORIL. Do not drive or do other
dangerous activities after taking RESTORIL until you feel fully awake.
• You may have withdrawal symptoms if you stop taking RESTORIL suddenly. Withdrawal
symptoms can be serious and include seizures. Mild withdrawal symptoms include a
depressed mood and trouble sleeping. Talk to your doctor to check if you need to stop
RESTORIL slowly.
These are not all the side effects of RESTORIL. Ask your doctor or pharmacist for more
information.
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NDA 18163 FDA Approved Labeling text 11.4.10
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store RESTORIL?
• Store RESTORIL at room temperature, 68° to 77°F (20° to 25°C).
• Keep RESTORIL and all medicines out of reach of children.
General Information about RESTORIL
• Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide.
• Do not use RESTORIL for a condition for which it was not prescribed.
• Do not share RESTORIL with other people, even if you think they have the same symptoms
that you have. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about RESTORIL. If you
would like more information, talk with your doctor. You can ask your doctor or pharmacist for
information about RESTORIL that is written for healthcare professionals, or you may also
contact Mallinckrodt (the maker of RESTORIL) by visiting www.Mallinckrodt.com or calling
1-800-778-7898.
What are the ingredients in RESTORIL?
7.5 mg, 15 mg, 22.5 mg, and 30 mg Capsules
Active Ingredient: temazepam USP
7.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, iron oxide red, shellac, shellac glaze, SD-35A alcohol.
15 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
22.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
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comp
any logo
NDA 18163 FDA Approved Labeling text 11.4.10
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
30 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
Rx only
This Medication Guide has been approved by the U.S. Food and Drug Administration.
RESTORIL is a trademark of Mallinckrodt Inc.
Mallinckrodt Inc.
Hazelwood, MO 63042 U.S.A.
Printed in U.S.A.
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|
custom-source
|
2025-02-12T13:44:38.324763
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018163s054lbl.pdf', 'application_number': 18163, 'submission_type': 'SUPPL ', 'submission_number': 54}
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1
2
EC-NAPROSYN® (naproxen delayed-release tablets)
3
NAPROSYN® (naproxen tablets)
4
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
5
NAPROSYN® (naproxen suspension) Roche Logo
6
Rx only
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk
may increase with duration of use. Patients with cardiovascular disease or
risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
• Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS or NAPROSYN Suspension is contraindicated for the treatment of
peri-operative pain in the setting of coronary artery bypass graft (CABG)
surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or
intestines, which can be fatal. These events can occur at any time during
use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
7
DESCRIPTION
8
Naproxen is a proprionic acid derivative related to the arylacetic acid group of
9
nonsteroidal anti-inflammatory drugs.
10
The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α
11
methyl-2-naphthaleneacetic
acid
and
(S)-6-methoxy-α-methyl-2
12
naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen
13
sodium have the following structures, respectively:
Chemical Structure
15
Naproxen has a molecular weight of 230.26 and a molecular formula of
16
C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a
17
molecular formula of C14H13NaO3.
18
Naproxen is an odorless, white to off-white crystalline substance. It is lipid
19
soluble, practically insoluble in water at low pH and freely soluble in water at
20
high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
21
to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely
22
soluble in water at neutral pH.
23
NAPROSYN (naproxen tablets) is available as yellow tablets containing 250
24
mg of naproxen, pink tablets containing 375 mg of naproxen and yellow
25
tablets containing 500 mg of naproxen for oral administration. The inactive
26
ingredients are croscarmellose sodium, iron oxides, povidone and magnesium
27
stearate.
28
EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric
29
coated white tablets containing 375 mg of naproxen and 500 mg of naproxen
30
for oral administration. The inactive ingredients are croscarmellose sodium,
31
povidone and magnesium stearate. The enteric coating dispersion contains
32
methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and
33
purified water. The dissolution of this enteric-coated naproxen tablet is pH
34
dependent with rapid dissolution above pH 6. There is no dissolution below
35
pH 4.
36
ANAPROX (naproxen sodium tablets) is available as blue tablets containing
37
275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is
38
available as dark blue tablets containing 550 mg of naproxen sodium for oral
39
administration.
The
inactive
ingredients
are
magnesium
stearate,
40
microcrystalline cellulose, povidone and talc. The coating suspension for the
41
ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910,
42
Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The
43
coating suspension for the ANAPROX DS 550 mg tablet may contain
44
hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene
45
glycol 8000 or Opadry YS-1-4216.
46
NAPROSYN (naproxen suspension) is available as a light orange-colored
47
opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle
48
containing sucrose, magnesium aluminum silicate, sorbitol solution and
49
sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C
50
Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified
51
water. The pH of the suspension ranges from 2.2 to 3.7.
52
CLINICAL PHARMACOLOGY
53
Pharmacodynamics
54
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic
55
and antipyretic properties. The sodium salt of naproxen has been developed as
56
a more rapidly absorbed formulation of naproxen for use as an analgesic. The
57
mechanism of action of the naproxen anion, like that of other NSAIDs, is not
58
completely understood but may be related to prostaglandin synthetase
59
inhibition.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
60
Pharmacokinetics
61
Naproxen and naproxen sodium are rapidly and completely absorbed from the
62
gastrointestinal tract with an in vivo bioavailability of 95%. The different
63
dosage forms of NAPROSYN are bioequivalent in terms of extent of
64
absorption (AUC) and peak concentration (Cmax); however, the products do
65
differ in their pattern of absorption. These differences between naproxen
66
products are related to both the chemical form of naproxen used and its
67
formulation. Even with the observed differences in pattern of absorption, the
68
elimination half-life of naproxen is unchanged across products ranging from
69
12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and
70
the degree of naproxen accumulation is consistent with this half-life. This
71
suggests that the differences in pattern of release play only a negligible role in
72
the attainment of steady-state plasma levels.
73
Absorption
74
Immediate Release
75
After administration of NAPROSYN tablets, peak plasma levels are attained
76
in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels
77
are attained in 1 to 2 hours. The difference in rates between the two products
78
is due to the increased aqueous solubility of the sodium salt of naproxen used
79
in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN
80
Suspension are attained in 1 to 4 hours.
81
Delayed Release
82
EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier
83
to disintegration in the acidic environment of the stomach and to lose integrity
84
in the more neutral environment of the small intestine. The enteric polymer
85
coating selected for EC-NAPROSYN dissolves above pH 6. When EC
86
NAPROSYN was given to fasted subjects, peak plasma levels were attained
87
about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo
88
study in man using radiolabeled EC-NAPROSYN tablets demonstrated that
89
EC-NAPROSYN dissolves primarily in the small intestine rather than in the
90
stomach, so the absorption of the drug is delayed until the stomach is emptied.
91
When EC-NAPROSYN and NAPROSYN were given to fasted subjects
92
(n=24) in a crossover study following 1 week of dosing, differences in time to
93
peak plasma levels (Tmax) were observed, but there were no differences in total
94
absorption as measured by Cmax and AUC:
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
EC-NAPROSYN*
500 mg bid
NAPROSYN*
500 mg bid
Cmax (µg/mL)
Tmax (hours)
AUC0–12 hr (µg·hr/mL)
94.9 (18%)
4 (39%)
845 (20%)
97.4 (13%)
1.9 (61%)
767 (15%)
95
*Mean value (coefficient of variation)
96
Antacid Effects
97
When EC-NAPROSYN was given as a single dose with antacid (54 mEq
98
buffering capacity), the peak plasma levels of naproxen were unchanged, but
99
the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with
100
antacid 5 hours), although not significantly.
101
Food Effects
102
When EC-NAPROSYN was given as a single dose with food, peak plasma
103
levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours).
104
Residence time in the small intestine until disintegration was independent of
105
food intake. The presence of food prolonged the time the tablets remained in
106
the stomach, time to first detectable serum naproxen levels, and time to
107
maximal naproxen levels (Tmax), but did not affect peak naproxen levels
108
(Cmax).
109
Distribution
110
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels
111
naproxen is greater than 99% albumin-bound. At doses of naproxen greater
112
than 500 mg/day there is less than proportional increase in plasma levels due
113
to an increase in clearance caused by saturation of plasma protein binding at
114
higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and
115
1500 mg daily doses of naproxen, respectively). The naproxen anion has been
116
found in the milk of lactating women at a concentration equivalent to
117
approximately 1% of maximum naproxen concentration in plasma (see
118
PRECAUTIONS: Nursing Mothers).
119
Metabolism
120
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen,
121
and both parent and metabolites do not induce metabolizing enzymes. Both
122
naproxen and 6-0-desmethyl naproxen are further metabolized to their
123
respective acylglucuronide conjugated metabolites.
124
Excretion
125
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the
126
naproxen from any dose is excreted in the urine, primarily as naproxen (<1%),
127
6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
128
half-life of the naproxen anion in humans ranges from 12 to 17 hours. The
129
corresponding half-lives of both naproxen’s metabolites and conjugates are
130
shorter than 12 hours, and their rates of excretion have been found to coincide
131
closely with the rate of naproxen disappearance from the plasma. Small
132
amounts, 3% or less of the administered dose, are excreted in the feces. In
133
patients with renal failure metabolites may accumulate (see WARNINGS:
134
Renal Effects).
135
Special Populations
136
Pediatric Patients
137
In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels
138
following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND
139
ADMINISTRATION) were found to be similar to those found in normal
140
adults following a 500 mg dose. The terminal half-life appears to be similar in
141
pediatric and adult patients. Pharmacokinetic studies of naproxen were not
142
performed in pediatric patients younger than 5 years of age. Pharmacokinetic
143
parameters appear to be similar following administration of naproxen
144
suspension or tablets in pediatric patients. EC-NAPROSYN has not been
145
studied in subjects under the age of 18.
146
Geriatric Patients
147
Studies indicate that although total plasma concentration of naproxen is
148
unchanged, the unbound plasma fraction of naproxen is increased in the
149
elderly, although the unbound fraction is <1% of the total naproxen
150
concentration. Unbound trough naproxen concentrations in elderly subjects
151
have been reported to range from 0.12% to 0.19% of total naproxen
152
concentration, compared with 0.05% to 0.075% in younger subjects. The
153
clinical significance of this finding is unclear, although it is possible that the
154
increase in free naproxen concentration could be associated with an increase
155
in the rate of adverse events per a given dosage in some elderly patients.
156
Race
157
Pharmacokinetic differences due to race have not been studied.
158
Hepatic Insufficiency
159
Naproxen pharmacokinetics has not been determined in subjects with hepatic
160
insufficiency.
161
Renal Insufficiency
162
Naproxen pharmacokinetics has not been determined in subjects with renal
163
insufficiency. Given that naproxen, its metabolites and conjugates are
164
primarily excreted by the kidney, the potential exists for naproxen metabolites
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
165
to accumulate in the presence of renal insufficiency. Elimination of naproxen
166
is decreased in patients with severe renal impairment. Naproxen-containing
167
products are not recommended for use in patients with moderate to severe and
168
severe
renal
impairment
(creatinine
clearance
<30
mL/min)
(see
169
WARNINGS: Renal Effects).
170
CLINICAL STUDIES
171
General Information
172
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis,
173
juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute
174
gout. Improvement in patients treated for rheumatoid arthritis was
175
demonstrated by a reduction in joint swelling, a reduction in duration of
176
morning stiffness, a reduction in disease activity as assessed by both the
177
investigator and patient, and by increased mobility as demonstrated by a
178
reduction in walking time. Generally, response to naproxen has not been
179
found to be dependent on age, sex, severity or duration of rheumatoid arthritis.
180
In patients with osteoarthritis, the therapeutic action of naproxen has been
181
shown by a reduction in joint pain or tenderness, an increase in range of
182
motion in knee joints, increased mobility as demonstrated by a reduction in
183
walking time, and improvement in capacity to perform activities of daily
184
living impaired by the disease.
185
In a clinical trial comparing standard formulations of naproxen 375 mg bid
186
(750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group
187
terminated prematurely because of adverse events. Nineteen patients in the
188
1500 mg group terminated prematurely because of adverse events. Most of
189
these adverse events were gastrointestinal events.
190
In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and
191
juvenile arthritis, naproxen has been shown to be comparable to aspirin and
192
indomethacin in controlling the aforementioned measures of disease activity,
193
but the frequency and severity of the milder gastrointestinal adverse effects
194
(nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus,
195
dizziness, lightheadedness) were less in naproxen-treated patients than in
196
those treated with aspirin or indomethacin.
197
In patients with ankylosing spondylitis, naproxen has been shown to decrease
198
night pain, morning stiffness and pain at rest. In double-blind studies the drug
199
was shown to be as effective as aspirin, but with fewer side effects.
200
In patients with acute gout, a favorable response to naproxen was shown by
201
significant clearing of inflammatory changes (eg, decrease in swelling, heat)
202
within 24 to 48 hours, as well as by relief of pain and tenderness.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
203
Naproxen has been studied in patients with mild to moderate pain secondary
204
to postoperative, orthopedic, postpartum episiotomy and uterine contraction
205
pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in
206
patients taking naproxen and within 30 minutes in patients taking naproxen
207
sodium. Analgesic effect was shown by such measures as reduction of pain
208
intensity scores, increase in pain relief scores, decrease in numbers of patients
209
requiring additional analgesic medication, and delay in time to remedication.
210
The analgesic effect has been found to last for up to 12 hours.
211
Naproxen may be used safely in combination with gold salts and/or
212
corticosteroids; however, in controlled clinical trials, when added to the
213
regimen of patients receiving corticosteroids, it did not appear to cause greater
214
improvement over that seen with corticosteroids alone. Whether naproxen has
215
a “steroid-sparing” effect has not been adequately studied. When added to the
216
regimen of patients receiving gold salts, naproxen did result in greater
217
improvement. Its use in combination with salicylates is not recommended
218
because there is evidence that aspirin increases the rate of excretion of
219
naproxen and data are inadequate to demonstrate that naproxen and aspirin
220
produce greater improvement over that achieved with aspirin alone. In
221
addition, as with other NSAIDs, the combination may result in higher
222
frequency of adverse events than demonstrated for either product alone.
223
In 51Cr blood loss and gastroscopy studies with normal volunteers, daily
224
administration of 1000 mg of naproxen as 1000 mg of NAPROSYN
225
(naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been
226
demonstrated to cause statistically significantly less gastric bleeding and
227
erosion than 3250 mg of aspirin.
228
Three 6-week, double-blind, multicenter studies with EC-NAPROSYN
229
(naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid,
230
n=279) were conducted comparing EC-NAPROSYN with NAPROSYN,
231
including 355 rheumatoid arthritis and osteoarthritis patients who had a recent
232
history of NSAID-related GI symptoms. These studies indicated that EC
233
NAPROSYN and NAPROSYN showed no significant differences in efficacy
234
or safety and had similar prevalence of minor GI complaints. Individual
235
patients, however, may find one formulation preferable to the other.
236
Five hundred and fifty-three patients received EC-NAPROSYN during long
237
term open-label trials (mean length of treatment was 159 days). The rates for
238
clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been
239
historically reported for long-term NSAID use.
240
Geriatric Patients
241
The hepatic and renal tolerability of long-term naproxen administration was
242
studied in two double-blind clinical trials involving 586 patients. Of the
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
243
patients studied, 98 patients were age 65 and older and 10 of the 98 patients
244
were age 75 and older. Naproxen was administered at doses of 375 mg twice
245
daily or 750 mg twice daily for up to 6 months. Transient abnormalities of
246
laboratory tests assessing hepatic and renal function were noted in some
247
patients, although there were no differences noted in the occurrence of
248
abnormal values among different age groups.
249
INDICATIONS AND USAGE
250
Carefully consider the potential benefits and risks of NAPROSYN, EC
251
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and
252
other treatment options before deciding to use NAPROSYN, EC
253
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use
254
the lowest effective dose for the shortest duration consistent with individual
255
patient treatment goals (see WARNINGS).
256
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
257
NAPROSYN Suspension is indicated:
258
• For the relief of the signs and symptoms of rheumatoid arthritis
259
• For the relief of the signs and symptoms of osteoarthritis
260
• For the relief of the signs and symptoms of ankylosing spondylitis
261
• For the relief of the signs and symptoms of juvenile arthritis
262
Naproxen as NAPROSYN Suspension is recommended for juvenile
263
rheumatoid arthritis in order to obtain the maximum dosage flexibility based
264
on the patient’s weight.
265
Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
266
Suspension is also indicated:
267
• For relief of the signs and symptoms of tendonitis
268
• For relief of the signs and symptoms of bursitis
269
• For relief of the signs and symptoms of acute gout
270
• For the management of pain
271
• For the management of primary dysmenorrhea
272
EC-NAPROSYN is not recommended for initial treatment of acute pain
273
because the absorption of naproxen is delayed compared to absorption from
274
other naproxen-containing products (see CLINICAL PHARMACOLOGY
275
and DOSAGE AND ADMINISTRATION).
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
276
CONTRAINDICATIONS
277
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
278
NAPROSYN Suspension are contraindicated in patients with known
279
hypersensitivity to naproxen and naproxen sodium.
280
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
281
NAPROSYN Suspension should not be given to patients who have
282
experienced asthma, urticaria, or allergic-type reactions after taking aspirin or
283
other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs
284
have been reported in such patients (see WARNINGS: Anaphylactoid
285
Reactions and PRECAUTIONS: Preexisting Asthma).
286
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
287
NAPROSYN Suspension are contraindicated for the treatment of peri
288
operative pain in the setting of coronary artery bypass graft (CABG) surgery
289
(see WARNINGS).
290
WARNINGS
291
CARDIOVASCULAR EFFECTS
292
Cardiovascular Thrombotic Events
293
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to
294
three years duration have shown an increased risk of serious cardiovascular
295
(CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.
296
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.
297
Patients with known CV disease or risk factors for CV disease may be at
298
greater risk. To minimize the potential risk for an adverse CV event in patients
299
treated with an NSAID, the lowest effective dose should be used for the
300
shortest duration possible. Physicians and patients should remain alert for the
301
development of such events, even in the absence of previous CV symptoms.
302
Patients should be informed about the signs and/or symptoms of serious CV
303
events and the steps to take if they occur.
304
There is no consistent evidence that concurrent use of aspirin mitigates the
305
increased risk of serious CV thrombotic events associated with NSAID use.
306
The concurrent use of aspirin and an NSAID does increase the risk of serious
307
GI events (see Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
308
Perforation).
309
Two large, controlled, clinical trials of a COX-2 selective NSAID for the
310
treatment of pain in the first 10-14 days following CABG surgery found an
311
increased
incidence
of
myocardial
infarction
and
stroke
(see
312
CONTRAINDICATIONS).
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
313
Hypertension
314
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
315
ANAPROX DS and NAPROSYN Suspension, can lead to onset of new
316
hypertension or worsening of pre-existing hypertension, either of which may
317
contribute to the increased incidence of CV events. Patients taking thiazides or
318
loop diuretics may have impaired response to these therapies when taking
319
NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
320
ANAPROX DS and NAPROSYN Suspension, should be used with caution in
321
patients with hypertension. Blood pressure (BP) should be monitored closely
322
during the initiation of NSAID treatment and throughout the course of
323
therapy.
324
Congestive Heart Failure and Edema
325
Fluid retention, edema, and peripheral edema have been observed in some
326
patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX,
327
ANAPROX DS and NAPROSYN Suspension should be used with caution in
328
patients with fluid retention, hypertension, or heart failure. Since each
329
ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium
330
(about 1 mEq per each 250 mg of naproxen), and each teaspoonful of
331
NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of
332
naproxen) of sodium, this should be considered in patients whose overall
333
intake of sodium must be severely restricted.
334
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
335
Perforation
336
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
337
ANAPROX DS and NAPROSYN Suspension, can cause serious
338
gastrointestinal (GI) adverse events including inflammation, bleeding,
339
ulceration, and perforation of the stomach, small intestine, or large intestine,
340
which can be fatal.
341
These serious adverse events can occur at any time, with or without warning
342
symptoms, in patients treated with NSAIDs. Only one in five patients, who
343
develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
344
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in
345
approximately 1% of patients treated for 3-6 months, and in about 2-4% of
346
patients treated for one year. These trends continue with longer duration of
347
use, increasing the likelihood of developing a serious GI event at some time
348
during the course of therapy. However, even short-term therapy is not without
349
risk. The utility of periodic laboratory monitoring has not been demonstrated,
350
nor has it been adequately assessed. Only 1 in 5 patients who develop a
351
serious upper GI adverse event on NSAID therapy is symptomatic.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
352
NSAIDs should be prescribed with extreme caution in those with a prior
353
history of ulcer disease or gastrointestinal bleeding. Patients with a prior
354
history of peptic ulcer disease and/or gastrointestinal bleeding who use
355
NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
356
compared to patients with neither of these risk factors. Other factors that
357
increase the risk for GI bleeding in patients treated with NSAIDs include
358
concomitant use of oral corticosteroids or anticoagulants, longer duration of
359
NSAID therapy, smoking, use of alcohol, older age, and poor general health
360
status. Most spontaneous reports of fatal GI events are in elderly or debilitated
361
patients and therefore, special care should be taken in treating this population.
362
To minimize the potential risk for an adverse GI event in patients treated with
363
an NSAID, the lowest effective dose should be used for the shortest possible
364
duration. Patients and physicians should remain alert for signs and symptoms
365
of GI ulceration and bleeding during NSAID therapy and promptly initiate
366
additional evaluation and treatment if a serious GI adverse event is suspected.
367
This should include discontinuation of the NSAID until a serious GI adverse
368
event is ruled out. For high risk patients, alternate therapies that do not
369
involve NSAIDs should be considered.
370
Epidemiological studies, both of the case-control and cohort design, have
371
demonstrated an association between use of psychotropic drugs that interfere
372
with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
373
In two studies, concurrent use of an NSAID or aspirin potentiated the risk of
374
bleeding (see PRECAUTIONS: Drug Interactions). Although these studies
375
focused on upper gastrointestinal bleeding, there is reason to believe that
376
bleeding at other sites may be similarly potentiated.
377
NSAIDs should be given with care to patients with a history of inflammatory
378
bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be
379
exacerbated.
380
Renal Effects
381
Long-term administration of NSAIDs has resulted in renal papillary necrosis
382
and other renal injury. Renal toxicity has also been seen in patients in whom
383
renal prostaglandins have a compensatory role in the maintenance of renal
384
perfusion.
In
these
patients,
administration
of
a
nonsteroidal
385
anti-inflammatory drug may cause a dose-dependent reduction in
386
prostaglandin formation and, secondarily, in renal blood flow, which may
387
precipitate overt renal decompensation. Patients at greatest risk of this
388
reaction are those with impaired renal function, hypovolemia, heart failure,
389
liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors,
390
and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug
391
therapy is usually followed by recovery to the pretreatment state (see
392
WARNINGS: Advanced Renal Disease).
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
393
Advanced Renal Disease
394
No information is available from controlled clinical studies regarding the use
395
of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
396
NAPROSYN Suspension in patients with advanced renal disease. Therefore,
397
treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS
398
and NAPROSYN Suspension is not recommended in these patients with
399
advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX,
400
ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close
401
monitoring of the patient’s renal function is advisable.
402
Anaphylactoid Reactions
403
As with other NSAIDs, anaphylactoid reactions may occur in patients without
404
known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX,
405
ANAPROX
DS
or
NAPROSYN
Suspension.
NAPROSYN,
EC
406
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
407
should not be given to patients with the aspirin triad. This symptom complex
408
typically occurs in asthmatic patients who experience rhinitis with or without
409
nasal polyps, or who exhibit severe, potentially fatal bronchospasm after
410
taking aspirin or other NSAIDs (see CONTRAINDICATIONS and
411
PRECAUTIONS: Preexisting Asthma). Emergency help should be sought
412
in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like
413
anaphylaxis, may have a fatal outcome.
414
Skin Reactions
415
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
416
ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse
417
events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and
418
toxic epidermal necrolysis (TEN), which can be fatal. These serious events
419
may occur without warning. Patients should be informed about the signs and
420
symptoms of serious skin manifestations and use of the drug should be
421
discontinued at the first appearance of skin rash or any other sign of
422
hypersensitivity.
423
Pregnancy
424
In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
425
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided
426
because it may cause premature closure of the ductus arteriosus.
427
PRECAUTIONS
428
General
429
Naproxen-containing products such as NAPROSYN, EC-NAPROSYN,
430
ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
431
other naproxen products should not be used concomitantly since they all
432
circulate in the plasma as the naproxen anion.
433
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
434
NAPROSYN Suspension cannot be expected to substitute for corticosteroids
435
or to treat corticosteroid insufficiency. Abrupt discontinuation of
436
corticosteroids may lead to disease exacerbation. Patients on prolonged
437
corticosteroid therapy should have their therapy tapered slowly if a decision is
438
made to discontinue corticosteroids and the patient should be observed closely
439
for any evidence of adverse effects, including adrenal insufficiency and
440
exacerbation of symptoms of arthritis.
441
Patients with initial hemoglobin values of 10 g or less who are to receive long
442
term therapy should have hemoglobin values determined periodically.
443
The
pharmacological
activity
of
NAPROSYN,
EC-NAPROSYN,
444
ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever
445
and inflammation may diminish the utility of these diagnostic signs in
446
detecting complications of presumed noninfectious, noninflammatory painful
447
conditions.
448
Because of adverse eye findings in animal studies with drugs of this class, it is
449
recommended that ophthalmic studies be carried out if any change or
450
disturbance in vision occurs.
451
Hepatic Effects
452
Borderline elevations of one or more liver tests may occur in up to 15% of
453
patients
taking
NSAIDs
including
NAPROSYN,
EC-NAPROSYN,
454
ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic
455
abnormalities may be the result of hypersensitivity rather than direct toxicity.
456
These laboratory abnormalities may progress, may remain essentially
457
unchanged, or may be transient with continued therapy. The SGPT (ALT) test
458
is probably the most sensitive indicator of liver dysfunction. Notable
459
elevations of ALT or AST (approximately three or more times the upper limit
460
of normal) have been reported in approximately 1% of patients in clinical
461
trials with NSAIDs. In addition, rare cases of severe hepatic reactions,
462
including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic
463
failure, some of them with fatal outcomes have been reported.
464
A patient with symptoms and/or signs suggesting liver dysfunction, or in
465
whom an abnormal liver test has occurred, should be evaluated for evidence
466
of the development of more severe hepatic reaction while on therapy with
467
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
or
468
NAPROSYN Suspension.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
469
If clinical signs and symptoms consistent with liver disease develop, or if
470
systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC
471
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension
472
should be discontinued.
473
Chronic alcoholic liver disease and probably other diseases with decreased or
474
abnormal plasma proteins (albumin) reduce the total plasma concentration of
475
naproxen, but the plasma concentration of unbound naproxen is increased.
476
Caution is advised when high doses are required and some adjustment of
477
dosage may be required in these patients. It is prudent to use the lowest
478
effective dose.
479
Hematological Effects
480
Anemia is sometimes seen in patients receiving NSAIDs, including
481
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
482
NAPROSYN Suspension. This may be due to fluid retention, occult or gross
483
GI blood loss, or an incompletely described effect upon erythropoiesis.
484
Patients on long-term treatment with NSAIDs, including NAPROSYN, EC
485
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension,
486
should have their hemoglobin or hematocrit checked if they exhibit any signs
487
or symptoms of anemia.
488
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding
489
time in some patients. Unlike aspirin, their effect on platelet function is
490
quantitatively less, of shorter duration, and reversible. Patients receiving either
491
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
or
492
NAPROSYN Suspension who may be adversely affected by alterations in
493
platelet function, such as those with coagulation disorders or patients
494
receiving anticoagulants, should be carefully monitored.
495
Preexisting Asthma
496
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in
497
patients with aspirin-sensitive asthma has been associated with severe
498
bronchospasm, which can be fatal. Since cross reactivity, including
499
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
500
drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC
501
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
502
should not be administered to patients with this form of aspirin sensitivity and
503
should be used with caution in patients with preexisting asthma.
504
Information for Patients
505
Patients should be informed of the following information before initiating
506
therapy with an NSAID and periodically during the course of ongoing
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
507
therapy. Patients should also be encouraged to read the NSAID
508
Medication Guide that accompanies each prescription dispensed.
509
1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
510
NAPROSYN Suspension, like other NSAIDs, may cause serious CV side
511
effects, such as MI or stroke, which may result in hospitalization and even
512
death. Although serious CV events can occur without warning symptoms,
513
patients should be alert for the signs and symptoms of chest pain,
514
shortness of breath, weakness, slurring of speech, and should ask for
515
medical advice when observing any indicative sign or symptoms. Patients
516
should be apprised of the importance of this follow-up (see WARNINGS:
517
Cardiovascular Effects).
518
2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
519
NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort
520
and, rarely, serious GI side effects, such as ulcers and bleeding, which
521
may result in hospitalization and even death. Although serious GI tract
522
ulcerations and bleeding can occur without warning symptoms, patients
523
should be alert for the signs and symptoms of ulcerations and bleeding,
524
and should ask for medical advice when observing any indicative sign or
525
symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
526
Patients should be apprised of the importance of this follow-up (see
527
WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding,
528
and Perforation).
529
3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
530
NAPROSYN Suspension, like other NSAIDs, can cause serious skin side
531
effects such as exfoliative dermatitis, SJS, and TEN, which may result in
532
hospitalizations and even death. Although serious skin reactions may
533
occur without warning, patients should be alert for the signs and
534
symptoms of skin rash and blisters, fever, or other signs of
535
hypersensitivity such as itching, and should ask for medical advice when
536
observing any indicative signs or symptoms. Patients should be advised to
537
stop the drug immediately if they develop any type of rash and contact
538
their physicians as soon as possible.
539
4. Patients should promptly report signs or symptoms of unexplained weight
540
gain or edema to their physicians.
541
5. Patients should be informed of the warning signs and symptoms of
542
hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper
543
quadrant tenderness, and “flu-like” symptoms). If these occur, patients
544
should be instructed to stop therapy and seek immediate medical therapy.
545
6. Patients should be informed of the signs of an anaphylactoid reaction (eg,
546
difficulty breathing, swelling of the face or throat). If these occur, patients
547
should be instructed to seek immediate emergency help (see
548
WARNINGS).
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
549
7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
550
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be
551
avoided because it may cause premature closure of the ductus arteriosus.
552
8. Caution should be exercised by patients whose activities require alertness
553
if they experience drowsiness, dizziness, vertigo or depression during
554
therapy with naproxen.
555
Laboratory Tests
556
Because serious GI tract ulcerations and bleeding can occur without warning
557
symptoms, physicians should monitor for signs or symptoms of GI bleeding.
558
Patients on long-term treatment with NSAIDs should have their CBC and a
559
chemistry profile checked periodically. If clinical signs and symptoms
560
consistent with liver or renal disease develop, systemic manifestations occur
561
(eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
562
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
563
NAPROSYN Suspension should be discontinued.
564
Drug Interactions
565
ACE-inhibitors
566
Reports suggest that NSAIDs may diminish the antihypertensive effect of
567
ACE-inhibitors. This interaction should be given consideration in patients
568
taking NSAIDs concomitantly with ACE-inhibitors.
569
Antacids and Sucralfate
570
Concomitant administration of some antacids (magnesium oxide or aluminum
571
hydroxide) and sucralfate can delay the absorption of naproxen.
572
Aspirin
573
When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
574
DS or NAPROSYN Suspension is administered with aspirin, its protein
575
binding is reduced, although the clearance of free NAPROSYN, EC
576
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is
577
not altered. The clinical significance of this interaction is not known;
578
however, as with other NSAIDs, concomitant administration of naproxen and
579
naproxen sodium and aspirin is not generally recommended because of the
580
potential of increased adverse effects.
581
Cholestyramine
582
As with other NSAIDs, concomitant administration of cholestyramine can
583
delay the absorption of naproxen.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
584
Diuretics
585
Clinical studies, as well as postmarketing observations, have shown that
586
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
587
NAPROSYN Suspension can reduce the natriuretic effect of furosemide and
588
thiazides in some patients. This response has been attributed to inhibition of
589
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
590
patient should be observed closely for signs of renal failure (see
591
WARNINGS: Renal Effects), as well as to assure diuretic efficacy.
592
Lithium
593
NSAIDs have produced an elevation of plasma lithium levels and a reduction
594
in renal lithium clearance. The mean minimum lithium concentration
595
increased 15% and the renal clearance was decreased by approximately 20%.
596
These effects have been attributed to inhibition of renal prostaglandin
597
synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
598
concurrently, subjects should be observed carefully for signs of lithium
599
toxicity.
600
Methotrexate
601
NSAIDs have been reported to competitively inhibit methotrexate
602
accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other
603
nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular
604
secretion of methotrexate in an animal model. This may indicate that they
605
could enhance the toxicity of methotrexate. Caution should be used when
606
NSAIDs are administered concomitantly with methotrexate.
607
Warfarin
608
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that
609
users of both drugs together have a risk of serious GI bleeding higher than
610
users of either drug alone. No significant interactions have been observed in
611
clinical studies with naproxen and coumarin-type anticoagulants. However,
612
caution is advised since interactions have been seen with other nonsteroidal
613
agents of this class. The free fraction of warfarin may increase substantially in
614
some subjects and naproxen interferes with platelet function.
615
Selective Serotonin Reuptake Inhibitors (SSRIs)
616
There is an increased risk of gastrointestinal bleeding when selective serotonin
617
reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be
618
used when NSAIDs are administered concomitantly with SSRIs.
619
Other Information Concerning Drug Interactions
620
Naproxen is highly bound to plasma albumin; it thus has a theoretical
621
potential for interaction with other albumin-bound drugs such as coumarin
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
622
type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
623
Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or
624
sulphonylurea should be observed for adjustment of dose if required.
625
Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the
626
antihypertensive effect of propranolol and other beta-blockers.
627
Probenecid given concurrently increases naproxen anion plasma levels and
628
extends its plasma half-life significantly.
629
Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive
630
antacid therapy, concomitant administration of EC-NAPROSYN is not
631
recommended.
632
Drug/Laboratory Test Interaction
633
Naproxen may decrease platelet aggregation and prolong bleeding time. This
634
effect should be kept in mind when bleeding times are determined.
635
The administration of naproxen may result in increased urinary values for 17
636
ketogenic steroids because of an interaction between the drug and/or its
637
metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy
638
corticosteroid measurements (Porter-Silber test) do not appear to be
639
artifactually altered, it is suggested that therapy with naproxen be temporarily
640
discontinued 72 hours before adrenal function tests are performed if the
641
Porter-Silber test is to be used.
642
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic
643
acid (5HIAA).
644
Carcinogenesis
645
A 2-year study was performed in rats to evaluate the carcinogenic potential of
646
naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2).
647
The maximum dose used was 0.28 times the systemic exposure to humans at
648
the recommended dose. No evidence of tumorigenicity was found.
649
Pregnancy
650
Teratogenic Effects
651
Pregnancy Category C
652
Reproduction studies have been performed in rats at 20 mg/kg/day
653
(125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20
654
mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and
655
mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic
656
exposure) with no evidence of impaired fertility or harm to the fetus due to the
657
drug. However, animal reproduction studies are not always predictive of
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
658
human response. There are no adequate and well-controlled studies in
659
pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
660
DS and NAPROSYN Suspension should be used in pregnancy only if the
661
potential benefit justifies the potential risk to the fetus.
662
Nonteratogenic Effects
663
There is some evidence to suggest that when inhibitors of prostaglandin
664
synthesis are used to delay preterm labor there is an increased risk of neonatal
665
complications such as necrotizing enterocolitis, patent ductus arteriosus and
666
intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay
667
parturition has been associated with persistent pulmonary hypertension, renal
668
dysfunction and abnormal prostaglandin E levels in preterm infants. Because
669
of the known effects of nonsteroidal anti-inflammatory drugs on the fetal
670
cardiovascular system (closure of ductus arteriosus), use during pregnancy
671
(particularly late pregnancy) should be avoided.
672
Labor and Delivery
673
In rat studies with NSAIDs, as with other drugs known to inhibit
674
prostaglandin synthesis, an increased incidence of dystocia, delayed
675
parturition, and decreased pup survival occurred. Naproxen-containing
676
products are not recommended in labor and delivery because, through its
677
prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal
678
circulation and inhibit uterine contractions, thus increasing the risk of uterine
679
hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX,
680
ANAPROX DS and NAPROSYN Suspension on labor and delivery in
681
pregnant women are unknown.
682
Nursing Mothers
683
The naproxen anion has been found in the milk of lactating women at a
684
concentration equivalent to approximately 1% of maximum naproxen
685
concentration in plasma. Because of the possible adverse effects of
686
prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be
687
avoided.
688
Pediatric Use
689
Safety and effectiveness in pediatric patients below the age of 2 years have
690
not been established. Pediatric dosing recommendations for juvenile arthritis
691
are
based
on
well-controlled
studies
(see
DOSAGE
AND
692
ADMINISTRATION). There are no adequate effectiveness or dose-response
693
data for other pediatric conditions, but the experience in juvenile arthritis and
694
other use experience have established that single doses of 2.5 to 5 mg/kg (as
695
naproxen suspension, see DOSAGE AND ADMINISTRATION), with total
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
696
daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients
697
over 2 years of age.
698
Geriatric Use
699
Studies indicate that although total plasma concentration of naproxen is
700
unchanged, the unbound plasma fraction of naproxen is increased in the
701
elderly. Caution is advised when high doses are required and some adjustment
702
of dosage may be required in elderly patients. As with other drugs used in the
703
elderly, it is prudent to use the lowest effective dose.
704
Experience indicates that geriatric patients may be particularly sensitive to
705
certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or
706
debilitated patients seem to tolerate peptic ulceration or bleeding less well
707
when these events do occur. Most spontaneous reports of fatal GI events are in
708
the geriatric population (see WARNINGS).
709
Naproxen is known to be substantially excreted by the kidney, and the risk of
710
toxic reactions to this drug may be greater in patients with impaired renal
711
function. Because elderly patients are more likely to have decreased renal
712
function, care should be taken in dose selection, and it may be useful to
713
monitor renal function. Geriatric patients may be at a greater risk for the
714
development of a form of renal toxicity precipitated by reduced prostaglandin
715
formation during administration of nonsteroidal anti-inflammatory drugs (see
716
WARNINGS: Renal Effects).
717
ADVERSE REACTIONS
718
Adverse reactions reported in controlled clinical trials in 960 patients treated
719
for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions
720
in patients treated chronically were reported 2 to 10 times more frequently
721
than they were in short-term studies in the 962 patients treated for mild to
722
moderate pain or for dysmenorrhea. The most frequent complaints reported
723
related to the gastrointestinal tract.
724
A clinical study found gastrointestinal reactions to be more frequent and more
725
severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen
726
compared
to
those
taking
750
mg
naproxen
(see
CLINICAL
727
PHARMACOLOGY).
728
In controlled clinical trials with about 80 pediatric patients and in well
729
monitored, open-label studies with about 400 pediatric patients with juvenile
730
arthritis treated with naproxen, the incidence of rash and prolonged bleeding
731
times were increased, the incidence of gastrointestinal and central nervous
732
system reactions were about the same, and the incidence of other reactions
733
were lower in pediatric patients than in adults.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
734
In patients taking naproxen in clinical trials, the most frequently reported
735
adverse experiences in approximately 1% to 10% of patients are:
736
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*,
737
nausea*, constipation*, diarrhea, dyspepsia, stomatitis
738
Central
Nervous
System:
headache*,
dizziness*,
drowsiness*,
739
lightheadedness, vertigo
740
Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating,
741
purpura
742
Special Senses: tinnitus*, visual disturbances, hearing disturbances
743
Cardiovascular: edema*, palpitations
744
General: dyspnea*, thirst
745
*Incidence of reported reaction between 3% and 9%. Those reactions
746
occurring in less than 3% of the patients are unmarked.
747
In patients taking NSAIDs, the following adverse experiences have also been
748
reported in approximately 1% to 10% of patients.
749
Gastrointestinal
(GI)
Experiences,
including:
flatulence,
gross
750
bleeding/perforation, GI ulcers (gastric/duodenal), vomiting
751
General: abnormal renal function, anemia, elevated liver enzymes, increased
752
bleeding time, rashes
753
The following are additional adverse experiences reported in <1% of patients
754
taking naproxen during clinical trials and through postmarketing reports.
755
Those adverse reactions observed through postmarketing reports are italicized.
756
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual
757
disorders, pyrexia (chills and fever)
758
Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary
759
edema
760
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis,
761
pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease
762
(ulcerative colitis, Crohn’s disease), nonpeptic gastrointestinal ulceration,
763
ulcerative stomatitis, esophagitis, peptic ulceration
764
Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases
765
have been fatal)
766
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia,
767
agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
768
Metabolic and Nutritional: hyperglycemia, hypoglycemia
769
Nervous System: inability to concentrate, depression, dream abnormalities,
770
insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive
771
dysfunction, convulsions
772
Respiratory: eosinophilic pneumonitis, asthma
773
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis,
774
erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus,
775
pustular reaction, systemic lupus erythematoses, bullous reactions, including
776
Stevens-Johnson
syndrome,
photosensitive
dermatitis,
photosensitivity
777
reactions, including rare cases resembling porphyria cutanea tarda
778
(pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or
779
other symptoms suggestive of pseudoporphyria occur, treatment should be
780
discontinued and the patient monitored.
781
Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar
782
optic neuritis, papilledema
783
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial
784
nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary
785
necrosis, raised serum creatinine
786
Reproduction (female): infertility
787
In patients taking NSAIDs, the following adverse experiences have also been
788
reported in <1% of patients.
789
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite
790
changes, death
791
Cardiovascular:
hypertension,
tachycardia,
syncope,
arrhythmia,
792
hypotension, myocardial infarction
793
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis,
794
glossitis, eructation
795
Hepatobiliary: hepatitis, liver failure
796
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
797
Metabolic and Nutritional: weight changes
798
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia,
799
somnolence, tremors, convulsions, coma, hallucinations
800
Respiratory: asthma, respiratory depression, pneumonia
801
Dermatologic: exfoliative dermatitis
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
802
Special Senses: blurred vision, conjunctivitis
803
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
804
OVERDOSAGE
805
Symptoms and Signs
806
Significant naproxen overdosage may be characterized by lethargy, dizziness,
807
drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion,
808
nausea, transient alterations in liver function, hypoprothrombinemia, renal
809
dysfunction,
metabolic
acidosis,
apnea,
disorientation
or
vomiting.
810
Gastrointestinal bleeding can occur. Hypertension, acute renal failure,
811
respiratory depression, and coma may occur, but are rare. Anaphylactoid
812
reactions have been reported with therapeutic ingestion of NSAIDs, and may
813
occur following an overdose. Because naproxen sodium may be rapidly
814
absorbed, high and early blood levels should be anticipated. A few patients
815
have experienced convulsions, but it is not clear whether or not these were
816
drug-related. It is not known what dose of the drug would be life threatening.
817
The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110
818
mg/kg in hamsters, and greater than 1000 mg/kg in dogs.
819
Treatment
820
Patients should be managed by symptomatic and supportive care following a
821
NSAID overdose. There are no specific antidotes. Hemodialysis does not
822
decrease the plasma concentration of naproxen because of the high degree of
823
its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1
824
to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients
825
seen within 4 hours of ingestion with symptoms or following a large overdose.
826
Forced diuresis, alkalinization of urine or hemoperfusion may not be useful
827
due to high protein binding.
828
DOSAGE AND ADMINISTRATION
829
Carefully consider the potential benefits and risks of NAPROSYN, EC
830
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and
831
other treatment options before deciding to use NAPROSYN, EC
832
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension.
833
Use the lowest effective dose for the shortest duration consistent with
834
individual patient treatment goals (see WARNINGS).
835
After observing the response to initial therapy with NAPROSYN, EC
836
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the
837
dose and frequency should be adjusted to suit an individual patient’s needs.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
838
Different dose strengths and formulations (ie, tablets, suspension) of the
839
drug are not necessarily bioequivalent. This difference should be taken
840
into consideration when changing formulation.
841
Although
NAPROSYN,
NAPROSYN
Suspension,
EC-NAPROSYN,
842
ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they
843
have pharmacokinetic differences that may affect onset of action. Onset of
844
pain relief can begin within 30 minutes in patients taking naproxen sodium
845
and within 1 hour in patients taking naproxen. Because EC-NAPROSYN
846
dissolves in the small intestine rather than in the stomach, the absorption of
847
the drug is delayed compared to the other naproxen formulations (see
848
CLINICAL PHARMACOLOGY).
849
The recommended strategy for initiating therapy is to choose a formulation
850
and a starting dose likely to be effective for the patient and then adjust the
851
dosage based on observation of benefit and/or adverse events. A lower dose
852
should be considered in patients with renal or hepatic impairment or in elderly
853
patients (see WARNINGS and PRECAUTIONS).
854
Geriatric Patients
855
Studies indicate that although total plasma concentration of naproxen is
856
unchanged, the unbound plasma fraction of naproxen is increased in the
857
elderly. Caution is advised when high doses are required and some adjustment
858
of dosage may be required in elderly patients. As with other drugs used in the
859
elderly, it is prudent to use the lowest effective dose.
860
Patients With Moderate to Severe Renal Impairment
861
Naproxen-containing products are not recommended for use in patients with
862
moderate to severe and severe renal impairment (creatinine clearance <30
863
mL/min) (see WARNINGS: Renal Effects).
864
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
NAPROSYN
250 mg
or 375 mg
or 500 mg
twice daily
twice daily
twice daily
ANAPROX
275 mg (naproxen 250 mg with 25 mg sodium)
twice daily
ANAPROX DS
550 mg (naproxen 500 mg with 50 mg sodium)
twice daily
NAPROSYN
Suspension
250 mg (10 mL/2 tsp)
or 375 mg (15 mL/3 tsp)
or 500 mg (20 mL/4 tsp)
twice daily
twice daily
twice daily
EC-NAPROSYN
375 mg
or 500 mg
twice daily
twice daily
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
865
To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet
866
should not be broken, crushed or chewed during ingestion. NAPROSYN
867
Suspension should be shaken gently before use.
868
During long-term administration, the dose of naproxen may be adjusted up or
869
down depending on the clinical response of the patient. A lower daily dose
870
may suffice for long-term administration. The morning and evening doses do
871
not have to be equal in size and the administration of the drug more frequently
872
than twice daily is not necessary.
873
In patients who tolerate lower doses well, the dose may be increased to
874
naproxen 1500 mg/day for limited periods of up to 6 months when a higher
875
level of anti-inflammatory/analgesic activity is required. When treating such
876
patients with naproxen 1500 mg/day, the physician should observe sufficient
877
increased clinical benefits to offset the potential increased risk. The morning
878
and evening doses do not have to be equal in size and administration of the
879
drug more frequently than twice daily does not generally make a difference in
880
response (see CLINICAL PHARMACOLOGY).
881
Juvenile Arthritis
882
The use of NAPROSYN Suspension is recommended for juvenile arthritis in
883
children 2 years or older because it allows for more flexible dose titration
884
based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day
885
produced plasma levels of naproxen similar to those seen in adults taking 500
886
mg of naproxen (see CLINICAL PHARMACOLOGY).
887
The recommended total daily dose of naproxen is approximately 10 mg/kg
888
given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup
889
marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the
890
NAPROSYN Suspension. The following table may be used as a guide for
891
dosing of NAPROSYN Suspension:
892
Patient’s Weight
Dose
Administered as
893
13 kg (29 lb)
62.5 mg bid 2.5 mL (1/2 tsp) twice daily
894
25 kg (55 lb)
125 mg bid 5.0 mL (1 tsp) twice daily
895
38 kg (84 lb)
187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily
896
Management of Pain, Primary Dysmenorrhea, and Acute
897
Tendonitis and Bursitis
898
The recommended starting dose is 550 mg of naproxen sodium as
899
ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg
900
every 6 to 8 hours as required. The initial total daily dose should not exceed
901
1375 mg of naproxen sodium. Thereafter, the total daily dose should not
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
902
exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is
903
more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the
904
management of acute painful conditions when prompt onset of pain relief is
905
desired. NAPROSYN may also be used but EC-NAPROSYN is not
906
recommended for initial treatment of acute pain because absorption of
907
naproxen is delayed compared to other naproxen-containing products (see
908
CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE).
909
Acute Gout
910
The recommended starting dose is 750 mg of NAPROSYN followed by 250
911
mg every 8 hours until the attack has subsided. ANAPROX may also be used
912
at a starting dose of 825 mg followed by 275 mg every 8 hours. EC
913
NAPROSYN is not recommended because of the delay in absorption (see
914
CLINICAL PHARMACOLOGY).
915
HOW SUPPLIED
916
NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR
917
LE 250 on one side and scored on the other. Packaged in light-resistant bottles
918
of 100.
919
100’s (bottle): NDC 0004-6313-01.
920
375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side.
921
Packaged in light-resistant bottles of 100.
922
100’s (bottle): NDC 0004-6314-01.
923
500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and
924
scored on the other. Packaged in light-resistant bottles of 100.
925
100’s (bottle): NDC 0004-6316-01.
926
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light
927
resistant containers.
928
NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5
929
mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC
930
0004-0028-28).
931
Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F).
932
Dispense in light-resistant containers. Shake gently before use.
933
EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex
934
coated tablets imprinted with NPR EC 375 on one side. Packaged in light
935
resistant bottles of 100.
936
100’s (bottle): NDC 0004-6415-01.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
937
500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side.
938
Packaged in light-resistant bottles of 100.
939
100’s (bottle): NDC 0004-6416-01.
940
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light
941
resistant containers.
942
ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped,
943
engraved with NPS-275 on one side. Packaged in bottles of 100.
944
100’s (bottle): NDC 0004-6202-01.
945
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
946
ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong
947
shaped, engraved with NPS 550 on one side and scored on both sides.
948
Packaged in bottles of 100.
949
100’s (bottle): NDC 0004-6203-01.
950
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
951
Revised: September 2007
952
953
Medication Guide
954
for
955
Non-steroidal Anti-Inflammatory Drugs (NSAIDs)
956
(See the end of this Medication Guide for a list of prescription NSAID
957
medicines.)
958
959
What is the most important information I should know about medicines
960
called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
961
NSAID medicines may increase the chance of a heart attack or
962
stroke that can lead to death. This chance increases:
963
• with longer use of NSAID medicines
964
• in people who have heart disease
965
966
NSAID medicines should never be used right before or after a
967
heart surgery called a “coronary artery bypass graft (CABG).”
968
NSAID medicines can cause ulcers and bleeding in the stomach
969
and intestines at any time during treatment. Ulcers and bleeding:
970
• can happen without warning symptoms
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
971
• may cause death
972
973
The chance of a person getting an ulcer or bleeding increases
974
with:
975
• taking medicines called “corticosteroids” and
976
“anticoagulants”
977
• longer use
978
• smoking
979
• drinking alcohol
980
• older age
981
• having poor health
982
983
NSAID medicines should only be used:
984
• exactly as prescribed
985
• at the lowest dose possible for your treatment
986
• for the shortest time needed
987
988
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
989
NSAID medicines are used to treat pain and redness, swelling, and heat
990
(inflammation) from medical conditions such as:
991
• different types of arthritis
992
• menstrual cramps and other types of short-term pain
993
994
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
995
Do not take an NSAID medicine:
996
• if you had an asthma attack, hives, or other allergic reaction with
997
aspirin or any other NSAID medicine
998
• for pain right before or after heart bypass surgery
999
1000
Tell your healthcare provider:
1001
• about all of your medical conditions.
1002
• about all of the medicines you take. NSAIDs and some other
1003
medicines can interact with each other and cause serious side
1004
effects. Keep a list of your medicines to show to your
1005
healthcare provider and pharmacist.
1006
• if you are pregnant. NSAID medicines should not be used by
1007
pregnant women late in their pregnancy.
1008
• if you are breastfeeding. Talk to your doctor.
1009
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
1010
What are the possible side effects of Non-Steroidal Anti-Inflammatory
1011
Drugs (NSAIDs)?
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling
(fluid retention)
•
kidney problems including kidney
failure
•
bleeding and ulcers in the stomach
and intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver
failure
•
asthma attacks in people who have
asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
1012
1013
Get emergency help right away if you have any of the following
1014
symptoms:
• shortness of breath or trouble
•
slurred speech
breathing
•
swelling of the face or
• chest pain
throat
• weakness in one part or side of your
body
1015
1016
Stop your NSAID medicine and call your healthcare provider right away
1017
if you have any of the following symptoms:
• nausea
•
there is blood in your
• more tired or weaker than usual
bowel movement or it is
• itching
black and sticky like tar
• your skin or eyes look yellow
•
unusual weight gain
• stomach pain
•
skin rash or blisters with
• flu-like symptoms
fever
• vomit blood
•
swelling of the arms and
legs, hands and feet
1018
1019
These are not all the side effects with NSAID medicines. Talk to your
1020
healthcare provider or pharmacist for more information about NSAID
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
1021
medicines. Call your doctor for medical advice about side effects. You may
1022
report side effects to FDA at 1-800-FDA-1088 or Roche at 1-800-526-6367.
1023
Other information about Non-Steroidal Anti-Inflammatory Drugs
1024
(NSAIDs):
1025
• Aspirin is an NSAID medicine but it does not increase the chance of a
1026
heart attack. Aspirin can cause bleeding in the brain, stomach, and
1027
intestines. Aspirin can also cause ulcers in the stomach and intestines.
1028
• Some of these NSAID medicines are sold in lower doses without a
1029
prescription (over-the-counter). Talk to your healthcare provider before
1030
using over-the-counter NSAIDs for more than 10 days.
1031
1032
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex®
Diclofenac
Cataflam®, Voltaren®, Arthrotec™ (combined with
misoprostol)
Diflunisal
Dolobid®
Etodolac
Lodine®, Lodine®XL
Fenoprofen
Nalfon®, Nalfon®200
Flurbirofen
Ansaid®
Ibuprofen
Motrin®, Tab-Profen®, Vicoprofen®* (combined with
hydrocodone), Combunox™ (combined with
oxycodone)
Indomethacin
Indocin®, Indocin®SR, Indo-Lemmon™,
Indomethagan™
Ketoprofen
Oruvail®
Ketorolac
Toradol®
Mefenamic Acid
Ponstel®
Meloxicam
Mobic®
Nabumetone
Relafen®
Naproxen
Naprosyn®, Anaprox®, Anaprox®DS, EC-Naprosyn® ,
Naprelan®, Naprapac® (copackaged with
lansoprazole)
Oxaprozin
Daypro®
Piroxicam
Feldene®
Sulindac
Clinoril®
Tolmetin
Tolectin®, Tolectin DS®, Tolectin®600
1033
*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC)
1034
NSAID, and is usually used for less than 10 days to treat pain. The OTC
1035
NSAID label warns that long term continuous use may increase the risk of
1036
heart attack or stroke.
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
1037
This Medication Guide has been approved by the U.S. Food and Drug
1038
Administration.
1039
Medication Guide Revised: Month Year
1040
1041
All registered trademarks in this document are the property of their respective
1042
owners.
1043
Distributed by:
Logo & Address
1045
1046
1047
XXXXXXXX
1048
Copyright © 1999-200X by Roche Laboratories Inc. All rights reserved.
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:38.440872
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017581s110,18164s60,18965s18,20067s17lbl.pdf', 'application_number': 18164, 'submission_type': 'SUPPL ', 'submission_number': 60}
|
11,175
|
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 1 of 15
Restoril™
(temazepam)
Capsules USP
Rx only
DESCRIPTION
Restoril™ (temazepam) is a benzodiazepine hypnotic agent. The chemical name is 7-chloro-
1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, and the structural
formula is:
C16H13ClN2O2 MW = 300.74
Temazepam is a white, crystalline substance, very slightly soluble in water and sparingly soluble
in alcohol USP.
Restoril™ (temazepam) capsules, 7.5 mg, 15 mg, 22.5 mg, and 30 mg, are for oral
administration.
7.5 mg, 15 mg, 22.5 mg, and 30 mg Capsules
Active Ingredient: temazepam USP
7.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, iron oxide red, shellac, shellac glaze, SD-35A alcohol.
15 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1 / Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 2 of 15
22.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1 / Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
30 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1 / Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
CLINICAL PHARMACOLOGY
Pharmacokinetics
In a single and multiple dose absorption, distribution, metabolism, and excretion (ADME) study,
using 3H labeled drug, Restoril was well absorbed and found to have minimal (8%) first pass
metabolism. There were no active metabolites formed and the only significant metabolite present
in blood was the O-conjugate. The unchanged drug was 96% bound to plasma proteins. The
blood level decline of the parent drug was biphasic with the short half-life ranging from 0.4 to
0.6 hours and the terminal half-life from 3.5 to 18.4 hours (mean 8.8 hours), depending on the
study population and method of determination. Metabolites were formed with a half-life of
10 hours and excreted with a half-life of approximately 2 hours. Thus, formation of the major
metabolite is the rate limiting step in the biodisposition of temazepam. There is no accumulation
of metabolites. A dose-proportional relationship has been established for the area under the
plasma concentration/time curve over the 15 to 30 mg dose range.
Temazepam was completely metabolized through conjugation prior to excretion; 80% to 90% of
the dose appeared in the urine. The major metabolite was the O-conjugate of temazepam (90%);
the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).
Bioavailability, Induction, and Plasma Levels
Following ingestion of a 30 mg Restoril capsule, measurable plasma concentrations were
achieved 10 to 20 minutes after dosing with peak plasma levels ranging from 666 to 982 ng/mL
(mean 865 ng/mL) occurring approximately 1.2 to 1.6 hours (mean 1.5 hours) after dosing.
In a 7 day study, in which subjects were given a 30 mg Restoril capsule 1 hour before retiring,
steady-state (as measured by the attainment of maximal trough concentrations) was achieved by
the third dose. Mean plasma levels of temazepam (for days 2 to 7) were 260±210 ng/mL at
9 hours and 75±80 ng/mL at 24 hours after dosing. A slight trend toward declining 24 hour
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 3 of 15
plasma levels was seen after day 4 in the study, however, the 24 hour plasma levels were quite
variable.
At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man.
Elimination Rate of Benzodiazepine Hypnotics and Profile of Common Untoward
Effects
The type and duration of hypnotic effects and the profile of unwanted effects during
administration of benzodiazepine hypnotics may be influenced by the biologic half-life of the
administered drug and for some hypnotics, the half-life of any active metabolites formed.
Benzodiazepine hypnotics have a spectrum of half-lives from short (<4 hours) to long
(>20 hours). When half-lives are long, drug (and for some drugs their active metabolites) may
accumulate during periods of nightly administration and be associated with impairments of
cognitive and/or motor performance during waking hours; the possibility of interaction with
other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are shorter, drug
(and, where appropriate, its active metabolites) will be cleared before the next dose is ingested,
and carry-over effects related to excessive sedation or CNS depression should be minimal or
absent. However, during nightly use for an extended period, pharmacodynamic tolerance or
adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a short
elimination half-life, it is possible that a relative deficiency of the drug, or, if appropriate, its
active metabolites (i.e., in relationship to the receptor site) may occur at some point in the
interval between each night’s use. This sequence of events may account for 2 clinical findings
reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine
hypnotics, namely, increased wakefulness during the last third of the night, and the appearance
of increased signs of daytime anxiety.
Controlled Trials Supporting Efficacy
Restoril improved sleep parameters in clinical studies. Residual medication effects (“hangover”)
were essentially absent. Early morning awakening, a particular problem in the geriatric patient,
was significantly reduced.
Patients with chronic insomnia were evaluated in 2 week, placebo controlled sleep laboratory
studies with Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime.
There was a linear dose-response improvement in total sleep time and sleep latency, with
significant drug-placebo differences at 2 weeks occurring only for total sleep time at the 2 higher
doses, and for sleep latency only at the highest dose.
In these sleep laboratory studies, REM sleep was essentially unchanged and slow wave sleep was
decreased. No measurable effects on daytime alertness or performance occurred following
Restoril treatment or during the withdrawal period, even though a transient sleep disturbance in
some sleep parameters was observed following withdrawal of the higher doses. There was no
evidence of tolerance development in the sleep laboratory parameters when patients were given
Restoril nightly for at least 2 weeks.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 4 of 15
In addition, normal subjects with transient insomnia associated with first night adaptation to the
sleep laboratory were evaluated in 24 hour, placebo controlled sleep laboratory studies with
Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. There was a
linear dose-response improvement in total sleep time, sleep latency and number of awakenings,
with significant drug-placebo differences occurring for sleep latency at all doses, for total sleep
time at the 2 higher doses and for number of awakenings only at the 30 mg dose.
INDICATIONS AND USAGE
Restoril™ (temazepam) is indicated for the short-term treatment of insomnia (generally 7 to 10
days).
For patients with short-term insomnia, instructions in the prescription should indicate that
Restoril™ (temazepam) should be used for short periods of time (7 to 10 days).
The clinical trials performed in support of efficacy were 2 weeks in duration with the final
formal assessment of sleep latency performed at the end of treatment.
CONTRAINDICATIONS
Benzodiazepines may cause fetal harm when administered to a pregnant woman. An increased
risk of congenital malformations associated with the use of diazepam and chlordiazepoxide
during the first trimester of pregnancy has been suggested in several studies. Transplacental
distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses
of a benzodiazepine hypnotic during the last weeks of pregnancy.
Reproduction studies in animals with temazepam were performed in rats and rabbits. In a
perinatal-postnatal study in rats, oral doses of 60 mg/kg/day resulted in increasing nursling
mortality. Teratology studies in rats demonstrated increased fetal resorptions at doses of 30 and
120 mg/kg in one study and increased occurrence of rudimentary ribs, which are considered
skeletal variants, in a second study at doses of 240 mg/kg or higher. In rabbits, occasional
abnormalities such as exencephaly and fusion or asymmetry of ribs were reported without dose
relationship. Although these abnormalities were not found in the concurrent control group, they
have been reported to occur randomly in historical controls. At doses of 40 mg/kg or higher,
there was an increased incidence of the 13th rib variant when compared to the incidence in
concurrent and historical controls.
Restoril is contraindicated in women who are or may become pregnant. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential hazard to the fetus. Patients should be instructed to discontinue the drug
prior to becoming pregnant. The possibility that a woman of childbearing potential may be
pregnant at the time of institution of therapy should be considered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 5 of 15
WARNINGS
Sleep disturbance may be the presenting manifestation of an underlying physical and/or
psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia
should only be made after the patient has been carefully evaluated. The failure of insomnia to
remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric
and/or medical illness that should be evaluated. Worsening of insomnia may be the
consequence of an unrecognized psychiatric or physical disorder as may the emergence of new
abnormalities of thinking or behavior. Such abnormalities have also been reported to occur in
association with the use of drugs with central nervous system depressant activity, including those
of the benzodiazepine class. Because some of the worrisome adverse effects of benzodiazepines,
including Restoril, appear to be dose related (see PRECAUTIONS and DOSAGE AND
ADMINISTRATION), it is important to use the lowest possible effective dose. Elderly patients
are especially at risk.
Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and
extroversion that seem out of character, similar to that seen with alcohol. Other kinds of
behavioral changes can also occur, for example, bizarre behavior, agitation, hallucinations, and
depersonalization. Complex behaviors such as “sleep-driving” (i.e., driving while not fully
awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported.
These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced
persons. Although behaviors such as sleep-driving may occur with Restoril alone at therapeutic
doses, the use of alcohol and other CNS depressants with Restoril appears to increase the risk of
such behaviors, as does the use of Restoril at doses exceeding the maximum recommended dose.
Due to the risk to the patient and the community, discontinuation of Restoril should be strongly
considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g.,
preparing and eating food, making phone calls, or having sex) have been reported in patients
who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually
do not remember these events. Amnesia and other neuro-psychiatric symptoms may occur
unpredictably. In primarily depressed patients, worsening of depression, including suicidal
thinking has been reported in association with the use of sedative/hypnotics.
It can rarely be determined with certainty whether a particular instance of the abnormal
behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying
psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or
symptom of concern requires careful and immediate evaluation.
Withdrawal symptoms (of the barbiturate type) have occurred after the abrupt discontinuation of
benzodiazepines (see DRUG ABUSE AND DEPENDENCE).
Severe Anaphylactic and Anaphylactoid Reactions
Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients
after taking the first or subsequent doses of sedative-hypnotics, including Restoril. Some patients
have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that
suggest anaphylaxis. Some patients have required medical therapy in the emergency department.
If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 6 of 15
Patients who develop angioedema after treatment with Restoril should not be rechallenged with
the drug.
PRECAUTIONS
General
Since the risk of the development of oversedation, dizziness, confusion, and/or ataxia increases
substantially with larger doses of benzodiazepines in elderly and debilitated patients, 7.5 mg of
Restoril is recommended as the initial dosage for such patients.
Restoril should be administered with caution in severely depressed patients or those in whom
there is any evidence of latent depression; it should be recognized that suicidal tendencies may
be present and protective measures may be necessary.
The usual precautions should be observed in patients with impaired renal or hepatic function and
in patients with chronic pulmonary insufficiency.
If Restoril is to be combined with other drugs having known hypnotic properties or CNS-
depressant effects, consideration should be given to potential additive effects.
The possibility of a synergistic effect exists with the co-administration of Restoril and
diphenhydramine. One case of stillbirth at term has been reported 8 hours after a pregnant patient
received Restoril and diphenhydramine. A cause and effect relationship has not yet been
determined (see CONTRAINDICATIONS).
Information for Patients
The text of a patient Medication Guide is printed at the end of this insert. To assure safe and
effective use of Restoril, the information and instructions provided in this patient Medication
Guide should be discussed with patients.
Special Concerns
“Sleep-Driving” and Other Complex Behaviors – There have been reports of people getting
out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often
with no memory of the event. If a patient experiences such an episode, it should be reported to
his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more
likely to occur when Restoril is taken with alcohol or other central nervous system depressants
(see WARNINGS). Other complex behaviors (e.g., preparing and eating food, making phone
calls, or having sex) have been reported in patients who are not fully awake after taking a
sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.
Laboratory Tests
The usual precautions should be observed in patients with impaired renal or hepatic function and
in patients with chronic pulmonary insufficiency. Abnormal liver function tests as well as blood
dyscrasias have been reported with benzodiazepines.
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18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 7 of 15
Drug Interactions
The pharmacokinetic profile of temazepam does not appear to be altered by orally administered
cimetidine dosed according to labeling.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in rats at dietary temazepam doses up to 160 mg/kg/day
for 24 months and in mice at dietary doses of 160 mg/kg/day for 18 months. No evidence of
carcinogenicity was observed although hyperplastic liver nodules were observed in female mice
exposed to the highest dose. The clinical significance of this finding is not known.
Fertility in male and female rats was not adversely affected by Restoril.
No mutagenicity tests have been done with temazepam.
Pregnancy
Pregnancy Category X (see CONTRAINDICATIONS).
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Restoril is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
During controlled clinical studies in which 1076 patients received Restoril at bedtime, the drug
was well tolerated. Side effects were usually mild and transient. Adverse reactions occurring in
1% or more of patients are presented in the following table:
Restoril
% Incidence
(n=1076)
Placebo
% Incidence
(n=783)
Drowsiness
9.1
5.6
Headache
8.5
9.1
Fatigue
4.8
4.7
Nervousness
4.6
8.2
Lethargy
4.5
3.4
Dizziness
4.5
3.3
Nausea
3.1
3.8
Hangover
2.5
1.1
Anxiety
2.0
1.5
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18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 8 of 15
Depression
1.7
1.8
Dry Mouth
1.7
2.2
Diarrhea
1.7
1.1
Abdominal Discomfort
1.5
1.9
Euphoria
1.5
0.4
Weakness
1.4
0.9
Confusion
1.3
0.5
Blurred Vision
1.3
1.3
Nightmares
1.2
1.7
Vertigo
1.2
0.8
The following adverse events have been reported less frequently (0.5% to 0.9%):
Central Nervous System – anorexia, ataxia, equilibrium loss, tremor, increased dreaming
Cardiovascular – dyspnea, palpitations
Gastrointestinal – vomiting
Musculoskeletal – backache
Special Senses – hyperhidrosis, burning eyes
Amnesia, hallucinations, horizontal nystagmus, and paradoxical reactions including restlessness,
overstimulation and agitation were rare (less than 0.5%).
DRUG ABUSE AND DEPENDENCE
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is
characterized by misuse of the drug for non-medical purposes, often in combination with other
psychoactive substances. Physical dependence is a state of adaptation that is manifested by a
specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction,
decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of
adaptation in which exposure to a drug induces changes that result in a diminution of one or
more of the drug’s effects over time. Tolerance may occur to both the desired and undesired
effects of drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use, compulsive
use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a
multidisciplinary approach, but relapse is common.
Controlled Substance
Restoril is a controlled substance in Schedule IV.
Abuse and Dependence
Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol
(convulsions, tremor, abdominal, and muscle cramps, vomiting, and sweating), have occurred
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18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 9 of 15
following abrupt discontinuance of benzodiazepines. The more severe withdrawal symptoms
have usually been limited to those patients who received excessive doses over an extended
period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been
reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic
levels for several months. Consequently, after extended therapy at doses higher than 15 mg,
abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule
followed. As with any hypnotic, caution must be exercised in administering Restoril to
individuals known to be addiction-prone or to those whose history suggests they may increase
the dosage on their own initiative. It is desirable to limit repeated prescriptions without adequate
medical supervision.
OVERDOSAGE
Manifestations of acute overdosage of Restoril can be expected to reflect the CNS effects of the
drug and include somnolence, confusion, and coma, with reduced or absent reflexes, respiratory
depression, and hypotension. The oral LD50 of Restoril was 1963 mg/kg in mice, 1833 mg/kg in
rats, and >2400 mg/kg in rabbits.
Treatment
If the patient is conscious, vomiting should be induced mechanically or with emetics. Gastric
lavage should be employed utilizing concurrently a cuffed endotracheal tube if the patient is
unconscious to prevent aspiration and pulmonary complications. Maintenance of adequate
pulmonary ventilation is essential. The use of pressor agents intravenously may be necessary to
combat hypotension. Fluids should be administered intravenously to encourage diuresis. The
value of dialysis has not been determined. If excitation occurs, barbiturates should not be used. It
should be borne in mind that multiple agents may have been ingested. Flumazenil
(Romazicon®)*, a specific benzodiazepine receptor antagonist, is indicated for the complete or
partial reversal of the sedative effects of benzodiazepines and may be used in situations when an
overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil,
necessary measures should be instituted to secure airway, ventilation, and intravenous access.
Flumazenil is intended as an adjunct to, not as a substitute for, proper management of
benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation,
respiratory depression, and other residual benzodiazepine effects for an appropriate period after
treatment. The prescriber should be aware of a risk of seizure in association with flumazenil
treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant
overdose. The complete flumazenil package insert including CONTRAINDICATIONS,
WARNINGS, and PRECAUTIONS should be consulted prior to use.
Up-to-date information about the treatment of overdose can often be obtained from a certified
Regional Poison Control Center. Telephone numbers of certified Regional Poison Control
Centers are listed in the Physicians’ Desk Reference®**.
DOSAGE AND ADMINISTRATION
While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for
some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 10 of 15
sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that
therapy be initiated with 7.5 mg until individual responses are determined.
HOW SUPPLIED
Restoril™ (temazepam) Capsules USP
7.5 mg
Blue and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and M® on the
other side in red, and a blue cap imprinted “RESTORIL 7.5 mg” twice in red.
Bottle of 100 . . . . . . . . .NDC 0406-9915-01
15 mg
Maroon and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and M® on
the other side in red, and a maroon cap imprinted “RESTORIL 15 mg” twice in white.
Bottle of 100 . . . . . . . . .NDC 0406-9916-01
22.5 mg
Opaque blue capsules, with the opaque blue body imprinted “FOR SLEEP” on one side and M®
on the other side in red, and an opaque blue cap imprinted “RESTORIL 22.5 mg” twice in red.
Bottle of 30 . . . . . . . . . .NDC 0406-9914-03
30 mg
Maroon and blue capsules, with the blue body imprinted “FOR SLEEP” on one side and M® on
the other side in red, and a maroon cap imprinted “RESTORIL 30 mg” twice in white.
Bottle of 100 . . . . . . . . .NDC 0406-9917-01
Dispense in a well-closed, light-resistant container with a child-resistant closure.
Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
M and Restoril are trademarks of Mallinckrodt Inc.
*Romazicon is the registered trademark of Hoffman-LaRoche Inc.
**Trademark of Medical Economics Company, Inc.
Mallinckrodt Inc.
Hazelwood, MO 63042 U.S.A.
Rev 012908
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For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 11 of 15
MEDICATION GUIDE
RESTORIL™ (res-tə-ril) Capsules
C-IV
(temazepam)
Read the Medication Guide that comes with RESTORIL before you start taking it and each time
you get a refill. There may be new information. This Medication Guide does not take the place
of talking to your doctor about your medical condition or treatment.
What is the most important information I should know about RESTORIL?
After taking RESTORIL, you may get up out of bed while not being fully awake and do an
activity that you do not know you are doing. The next morning, you may not remember
that you did anything during the night. You have a higher chance for doing these activities if
you drink alcohol or take other medicines that make you sleepy with RESTORIL. Reported
activities include:
• driving a car (“sleep-driving”)
• making and eating food
• talking on the phone
• having sex
• sleep-walking
Call your doctor right away if you find out that you have done any of the above activities
after taking RESTORIL.
Important:
1. Take RESTORIL exactly as prescribed
• Do not take more RESTORIL than prescribed.
• Take RESTORIL right before you get in bed, not sooner.
2. Do not take RESTORIL if you:
• drink alcohol
• take other medicines that can make you sleepy. Talk to your doctor about all of your
medicines. Your doctor will tell you if you can take RESTORIL with your other medicines
• cannot get a full night’s sleep
What is RESTORIL?
RESTORIL is a sedative-hypnotic (sleep) medicine. RESTORIL is used in adults for the short-
term (usually 7 to 10 days) treatment of a sleep problem called insomnia. Symptoms of
insomnia include:
• trouble falling asleep
• waking up often during the night
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18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 12 of 15
RESTORIL is not for children.
RESTORIL is a federally controlled substance (C-IV) because it can be abused or lead to
dependence. Keep RESTORIL in a safe place to prevent misuse and abuse. Selling or giving
away RESTORIL may harm others, and is against the law. Tell your doctor if you have ever
abused or been dependent on alcohol, prescription medicines or street drugs.
Who should not take RESTORIL?
Do not take RESTORIL if you are pregnant or planning to become pregnant. RESTORIL
may cause birth defects or harm a fetus (unborn baby).
RESTORIL may not be right for you. Before starting RESTORIL, tell your doctor about
all of your health conditions, including if you:
• have a history of depression, mental illness, or suicidal thoughts
• have a history of drug or alcohol abuse or addiction
• have kidney or liver disease
• have a lung disease or breathing problems
• are breastfeeding
Tell your doctor about all of the medicines you take including prescription and nonprescription
medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes
causing serious side effects. Do not take RESTORIL with other medicines that can make
you sleepy.
Know the medicines you take. Keep a list of your medicines with you to show your doctor and
pharmacist each time you get a new medicine.
How should I take RESTORIL?
• Take RESTORIL exactly as prescribed. Do not take more RESTORIL than prescribed for
you.
• Take RESTORIL right before you get into bed.
• Do not take RESTORIL unless you are able to get a full night’s sleep before you must
be active again.
• Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may
mean that there is another condition causing your sleep problems.
• If you take too much RESTORIL or overdose, call your doctor or poison control center right
away, or get emergency treatment.
What are the possible side effects of RESTORIL?
Possible serious side effects of RESTORIL include:
• getting out of bed while not being fully awake and do an activity that you do not know
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For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 13 of 15
you are doing. (See “What is the most important information I should know about
RESTORIL?”)
• abnormal thoughts and behavior. Symptoms include more outgoing or aggressive
behavior than normal, confusion, agitation, hallucinations, worsening of depression, and
suicidal thoughts.
• memory loss
• anxiety
• severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble
breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms
after taking RESTORIL.
Call your doctor right away if you have any of the above side effects or any other side
effects that worry you while using RESTORIL.
The most common side effects of RESTORIL are:
• drowsiness
• headache
• tiredness
• nervousness
• dizziness
• nausea
• “hangover” feeling the day after taking RESTORIL
• You may still feel drowsy the next day after taking RESTORIL. Do not drive or do other
dangerous activities after taking RESTORIL until you feel fully awake.
• You may have withdrawal symptoms if you stop taking RESTORIL suddenly. Withdrawal
symptoms can be serious and include seizures. Mild withdrawal symptoms include a
depressed mood and trouble sleeping. Talk to your doctor to check if you need to stop
RESTORIL slowly.
These are not all the side effects of RESTORIL. Ask your doctor or pharmacist for more
information.
How should I store RESTORIL?
• Store RESTORIL at room temperature, 68° to 77°F (20° to 25°C).
• Keep RESTORIL and all medicines out of reach of children.
General Information about RESTORIL
• Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide.
• Do not use RESTORIL for a condition for which it was not prescribed.
• Do not share RESTORIL with other people, even if you think they have the same symptoms
that you have. It may harm them and it is against the law.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
Page 14 of 15
This Medication Guide summarizes the most important information about RESTORIL. If you
would like more information, talk with your doctor. You can ask your doctor or pharmacist for
information about RESTORIL that is written for healthcare professionals.
For more information, you may also contact Mallinckrodt (the maker of RESTORIL) by calling
the Mallinckrodt Medical Information Department at 1-800-778-7898.
What are the ingredients in RESTORIL?
7.5 mg, 15 mg, 22.5 mg, and 30 mg Capsules
Active Ingredient: temazepam USP
7.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, iron oxide red, shellac, shellac glaze, SD-35A alcohol.
15 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1 / Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
22.5 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1 / Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
30 mg Capsules
Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, red
iron oxide, titanium dioxide.
May also include: n-butyl alcohol, FD&C Blue #1 / Brilliant Blue FCF Aluminum Lake, iron
oxide red, isopropyl alcohol, propylene glycol, shellac, shellac glaze, SD-35A alcohol, SD-45
alcohol.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18163/S-058 S-059 FDA Approved Labeling Text 2.25.08
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Rx only
This Medication Guide has been approved by the U.S. Food and Drug Administration.
RESTORIL is a trademark of Mallinckrodt Inc.
Mallinckrodt Inc.
Hazelwood, MO 63042 U.S.A.
Printed in U.S.A.
[012908]
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:38.488312
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018163s058s059lbl.pdf', 'application_number': 18163, 'submission_type': 'SUPPL ', 'submission_number': 59}
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EC-NAPROSYN (naproxen delayed-release tablets)
NAPROSYN (naproxen tablets)
ANAPROX/ANAPROX DS (naproxen sodium tablets)
NAPROSYN (naproxen suspension)
Rx only
Cardiovascular Risk
NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk
may increase with duration of use. Patients with cardiovascular disease or
risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS or NAPROSYN Suspension is contraindicated for the treatment of
peri-operative pain in the setting of coronary artery bypass graft (CABG)
surgery (see WARNINGS).
Gastrointestinal Risk
NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or
intestines, which can be fatal. These events can occur at any time during
use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
DESCRIPTION
Naproxen is a proprionic acid derivative related to the arylacetic acid group of
nonsteroidal anti-inflammatory drugs.
The chemical names for naproxen and naproxen sodium are (S)-6-methoxy--
methyl-2-naphthaleneacetic
acid
and
(S)-6-methoxy--methyl-2-
naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen
sodium have the following structures, respectively:
Naproxen has a molecular weight of 230.26 and a molecular formula of
C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a
molecular formula of C14H13NaO3.
Naproxen is an odorless, white to off-white crystalline substance. It is lipid-
soluble, practically insoluble in water at low pH and freely soluble in water at
high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6
to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely
soluble in water at neutral pH.
1
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
NAPROSYN (naproxen tablets) is available as yellow tablets containing 250
mg of naproxen, pink tablets containing 375 mg of naproxen and yellow
tablets containing 500 mg of naproxen for oral administration. The inactive
ingredients are croscarmellose sodium, iron oxides, povidone and magnesium
stearate.
EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-
coated white tablets containing 375 mg of naproxen and 500 mg of naproxen
for oral administration. The inactive ingredients are croscarmellose sodium,
povidone and magnesium stearate. The enteric coating dispersion contains
methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and
purified water. The dissolution of this enteric-coated naproxen tablet is pH
dependent with rapid dissolution above pH 6. There is no dissolution below
pH 4.
ANAPROX (naproxen sodium tablets) is available as blue tablets containing
275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is
available as dark blue tablets containing 550 mg of naproxen sodium for oral
administration.
The
inactive
ingredients
are
magnesium
stearate,
microcrystalline cellulose, povidone and talc. The coating suspension for the
ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910,
Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The
coating suspension for the ANAPROX DS 550 mg tablet may contain
hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene
glycol 8000 or Opadry YS-1-4216.
NAPROSYN (naproxen suspension) is available as a light orange-colored
opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle
containing sucrose, magnesium aluminum silicate, sorbitol solution and
sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C
Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified
water. The pH of the suspension ranges from 2.2 to 3.7.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic
and antipyretic properties. The sodium salt of naproxen has been developed as
a more rapidly absorbed formulation of naproxen for use as an analgesic. The
mechanism of action of the naproxen anion, like that of other NSAIDs, is not
completely understood but may be related to prostaglandin synthetase
inhibition.
Pharmacokinetics
Naproxen and naproxen sodium are rapidly and completely absorbed from the
gastrointestinal tract with an in vivo bioavailability of 95%. The different
2
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
dosage forms of NAPROSYN are bioequivalent in terms of extent of
absorption (AUC) and peak concentration (Cmax); however, the products do
differ in their pattern of absorption. These differences between naproxen
products are related to both the chemical form of naproxen used and its
formulation. Even with the observed differences in pattern of absorption, the
elimination half-life of naproxen is unchanged across products ranging from
12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and
the degree of naproxen accumulation is consistent with this half-life. This
suggests that the differences in pattern of release play only a negligible role in
the attainment of steady-state plasma levels.
Absorption
Immediate Release
After administration of NAPROSYN tablets, peak plasma levels are attained
in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels
are attained in 1 to 2 hours. The difference in rates between the two products
is due to the increased aqueous solubility of the sodium salt of naproxen used
in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN
Suspension are attained in 1 to 4 hours.
Delayed Release
EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier
to disintegration in the acidic environment of the stomach and to lose integrity
in the more neutral environment of the small intestine. The enteric polymer
coating selected for EC-NAPROSYN dissolves above pH 6. When EC-
NAPROSYN was given to fasted subjects, peak plasma levels were attained
about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo
study in man using radiolabeled EC-NAPROSYN tablets demonstrated that
EC-NAPROSYN dissolves primarily in the small intestine rather than in the
stomach, so the absorption of the drug is delayed until the stomach is emptied.
When EC-NAPROSYN and NAPROSYN were given to fasted subjects
(n=24) in a crossover study following 1 week of dosing, differences in time to
peak plasma levels (Tmax) were observed, but there were no differences in total
absorption as measured by Cmax and AUC:
EC-NAPROSYN*
500 mg bid
NAPROSYN*
500 mg bid
Cmax (µg/mL)
94.9 (18%)
97.4 (13%)
Tmax (hours)
4 (39%)
1.9 (61%)
AUC0–12 hr (µg·hr/mL)
845 (20%)
767 (15%)
*Mean value (coefficient of variation)
3
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Antacid Effects
When EC-NAPROSYN was given as a single dose with antacid (54 mEq
buffering capacity), the peak plasma levels of naproxen were unchanged, but
the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with
antacid 5 hours), although not significantly.
Food Effects
When EC-NAPROSYN was given as a single dose with food, peak plasma
levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours).
Residence time in the small intestine until disintegration was independent of
food intake. The presence of food prolonged the time the tablets remained in
the stomach, time to first detectable serum naproxen levels, and time to
maximal naproxen levels (Tmax), but did not affect peak naproxen levels
(Cmax).
Distribution
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels
naproxen is greater than 99% albumin-bound. At doses of naproxen greater
than 500 mg/day there is less than proportional increase in plasma levels due
to an increase in clearance caused by saturation of plasma protein binding at
higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and
1500 mg daily doses of naproxen, respectively). The naproxen anion has been
found in the milk of lactating women at a concentration equivalent to
approximately 1% of maximum naproxen concentration in plasma (see
PRECAUTIONS: Nursing Mothers).
Metabolism
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen,
and both parent and metabolites do not induce metabolizing enzymes. Both
naproxen and 6-0-desmethyl naproxen are further metabolized to their
respective acylglucuronide conjugated metabolites.
Excretion
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the
naproxen from any dose is excreted in the urine, primarily as naproxen (<1%),
6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma
half-life of the naproxen anion in humans ranges from 12 to 17 hours. The
corresponding half-lives of both naproxen’s metabolites and conjugates are
shorter than 12 hours, and their rates of excretion have been found to coincide
closely with the rate of naproxen disappearance from the plasma. Small
amounts, 3% or less of the administered dose, are excreted in the feces. In
patients with renal failure metabolites may accumulate (see WARNINGS:
Renal Effects).
4
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Special Populations
Pediatric Patients
In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels
following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND
ADMINISTRATION) were found to be similar to those found in normal
adults following a 500 mg dose. The terminal half-life appears to be similar in
pediatric and adult patients. Pharmacokinetic studies of naproxen were not
performed in pediatric patients younger than 5 years of age. Pharmacokinetic
parameters appear to be similar following administration of naproxen
suspension or tablets in pediatric patients. EC-NAPROSYN has not been
studied in subjects under the age of 18.
Geriatric Patients
Studies indicate that although total plasma concentration of naproxen is
unchanged, the unbound plasma fraction of naproxen is increased in the
elderly, although the unbound fraction is <1% of the total naproxen
concentration. Unbound trough naproxen concentrations in elderly subjects
have been reported to range from 0.12% to 0.19% of total naproxen
concentration, compared with 0.05% to 0.075% in younger subjects. The
clinical significance of this finding is unclear, although it is possible that the
increase in free naproxen concentration could be associated with an increase
in the rate of adverse events per a given dosage in some elderly patients.
Race
Pharmacokinetic differences due to race have not been studied.
Hepatic Insufficiency
Naproxen pharmacokinetics has not been determined in subjects with hepatic
insufficiency.
Renal Insufficiency
Naproxen pharmacokinetics has not been determined in subjects with renal
insufficiency. Given that naproxen, its metabolites and conjugates are
primarily excreted by the kidney, the potential exists for naproxen metabolites
to accumulate in the presence of renal insufficiency. Elimination of naproxen
is decreased in patients with severe renal impairment. Naproxen-containing
products are not recommended for use in patients with moderate to severe and
severe
renal
impairment
(creatinine
clearance
<30
mL/min)
(see
WARNINGS: Renal Effects).
CLINICAL STUDIES
General Information
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis,
juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute
5
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
gout. Improvement in patients treated for rheumatoid arthritis was
demonstrated by a reduction in joint swelling, a reduction in duration of
morning stiffness, a reduction in disease activity as assessed by both the
investigator and patient, and by increased mobility as demonstrated by a
reduction in walking time. Generally, response to naproxen has not been
found to be dependent on age, sex, severity or duration of rheumatoid arthritis.
In patients with osteoarthritis, the therapeutic action of naproxen has been
shown by a reduction in joint pain or tenderness, an increase in range of
motion in knee joints, increased mobility as demonstrated by a reduction in
walking time, and improvement in capacity to perform activities of daily
living impaired by the disease.
In a clinical trial comparing standard formulations of naproxen 375 mg bid
(750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group
terminated prematurely because of adverse events. Nineteen patients in the
1500 mg group terminated prematurely because of adverse events. Most of
these adverse events were gastrointestinal events.
In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and
juvenile arthritis, naproxen has been shown to be comparable to aspirin and
indomethacin in controlling the aforementioned measures of disease activity,
but the frequency and severity of the milder gastrointestinal adverse effects
(nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus,
dizziness, lightheadedness) were less in naproxen-treated patients than in
those treated with aspirin or indomethacin.
In patients with ankylosing spondylitis, naproxen has been shown to decrease
night pain, morning stiffness and pain at rest. In double-blind studies the drug
was shown to be as effective as aspirin, but with fewer side effects.
In patients with acute gout, a favorable response to naproxen was shown by
significant clearing of inflammatory changes (eg, decrease in swelling, heat)
within 24 to 48 hours, as well as by relief of pain and tenderness.
Naproxen has been studied in patients with mild to moderate pain secondary
to postoperative, orthopedic, postpartum episiotomy and uterine contraction
pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in
patients taking naproxen and within 30 minutes in patients taking naproxen
sodium. Analgesic effect was shown by such measures as reduction of pain
intensity scores, increase in pain relief scores, decrease in numbers of patients
requiring additional analgesic medication, and delay in time to remedication.
The analgesic effect has been found to last for up to 12 hours.
Naproxen may be used safely in combination with gold salts and/or
corticosteroids; however, in controlled clinical trials, when added to the
regimen of patients receiving corticosteroids, it did not appear to cause greater
6
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
improvement over that seen with corticosteroids alone. Whether naproxen has
a “steroid-sparing” effect has not been adequately studied. When added to the
regimen of patients receiving gold salts, naproxen did result in greater
improvement. Its use in combination with salicylates is not recommended
because there is evidence that aspirin increases the rate of excretion of
naproxen and data are inadequate to demonstrate that naproxen and aspirin
produce greater improvement over that achieved with aspirin alone. In
addition, as with other NSAIDs, the combination may result in higher
frequency of adverse events than demonstrated for either product alone.
In 51Cr blood loss and gastroscopy studies with normal volunteers, daily
administration of 1000 mg of naproxen as 1000 mg of NAPROSYN
(naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been
demonstrated to cause statistically significantly less gastric bleeding and
erosion than 3250 mg of aspirin.
Three 6-week, double-blind, multicenter studies with EC-NAPROSYN
(naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid,
n=279) were conducted comparing EC-NAPROSYN with NAPROSYN,
including 355 rheumatoid arthritis and osteoarthritis patients who had a recent
history of NSAID-related GI symptoms. These studies indicated that EC-
NAPROSYN and NAPROSYN showed no significant differences in efficacy
or safety and had similar prevalence of minor GI complaints. Individual
patients, however, may find one formulation preferable to the other.
Five hundred and fifty-three patients received EC-NAPROSYN during long-
term open-label trials (mean length of treatment was 159 days). The rates for
clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been
historically reported for long-term NSAID use.
Geriatric Patients
The hepatic and renal tolerability of long-term naproxen administration was
studied in two double-blind clinical trials involving 586 patients. Of the
patients studied, 98 patients were age 65 and older and 10 of the 98 patients
were age 75 and older. Naproxen was administered at doses of 375 mg twice
daily or 750 mg twice daily for up to 6 months. Transient abnormalities of
laboratory tests assessing hepatic and renal function were noted in some
patients, although there were no differences noted in the occurrence of
abnormal values among different age groups.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and
other treatment options before deciding to use NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use
7
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
the lowest effective dose for the shortest duration consistent with individual
patient treatment goals (see WARNINGS).
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
NAPROSYN Suspension is indicated:
For the relief of the signs and symptoms of rheumatoid arthritis
For the relief of the signs and symptoms of osteoarthritis
For the relief of the signs and symptoms of ankylosing spondylitis
For the relief of the signs and symptoms of juvenile arthritis
Naproxen as NAPROSYN Suspension is recommended for juvenile
rheumatoid arthritis in order to obtain the maximum dosage flexibility based
on the patient’s weight.
Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
Suspension is also indicated:
For relief of the signs and symptoms of tendonitis
For relief of the signs and symptoms of bursitis
For relief of the signs and symptoms of acute gout
For the management of pain
For the management of primary dysmenorrhea
EC-NAPROSYN is not recommended for initial treatment of acute pain
because the absorption of naproxen is delayed compared to absorption from
other naproxen-containing products (see CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
NAPROSYN Suspension are contraindicated in patients with known
hypersensitivity to naproxen and naproxen sodium.
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
NAPROSYN Suspension should not be given to patients who have
experienced asthma, urticaria, or allergic-type reactions after taking aspirin or
other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs
have been reported in such patients (see WARNINGS: Anaphylactoid
Reactions and PRECAUTIONS: Preexisting Asthma).
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
NAPROSYN Suspension are contraindicated for the treatment of peri-
8
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
operative pain in the setting of coronary artery bypass graft (CABG) surgery
(see WARNINGS).
WARNINGS
Cardiovascular Effects
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to
three years duration have shown an increased risk of serious cardiovascular
(CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.
Patients with known CV disease or risk factors for CV disease may be at
greater risk. To minimize the potential risk for an adverse CV event in patients
treated with an NSAID, the lowest effective dose should be used for the
shortest duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV symptoms.
Patients should be informed about the signs and/or symptoms of serious CV
events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the
increased risk of serious CV thrombotic events associated with NSAID use.
The concurrent use of aspirin and an NSAID does increase the risk of serious
GI events (see WARNINGS: Gastrointestinal Effects – Risk of Ulceration,
Bleeding, and Perforation).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the
treatment of pain in the first 10-14 days following CABG surgery found an
increased
incidence
of
myocardial
infarction
and
stroke
(see
CONTRAINDICATIONS).
Hypertension
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX DS and NAPROSYN Suspension, can lead to onset of new
hypertension or worsening of pre-existing hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking thiazides or
loop diuretics may have impaired response to these therapies when taking
NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension, should be used with caution in
patients with hypertension. Blood pressure (BP) should be monitored closely
during the initiation of NSAID treatment and throughout the course of
therapy.
Congestive Heart Failure and Edema
Fluid retention, edema, and peripheral edema have been observed in some
patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension should be used with caution in
9
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
patients with fluid retention, hypertension, or heart failure. Since each
ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium
(about 1 mEq per each 250 mg of naproxen), and each teaspoonful of
NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of
naproxen) of sodium, this should be considered in patients whose overall
intake of sodium must be severely restricted.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
Perforation
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX DS and NAPROSYN Suspension, can cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal.
These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who
develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in
approximately 1% of patients treated for 3-6 months, and in about 2-4% of
patients treated for one year. These trends continue with longer duration of
use, increasing the likelihood of developing a serious GI event at some time
during the course of therapy. However, even short-term therapy is not without
risk. The utility of periodic laboratory monitoring has not been demonstrated,
nor has it been adequately assessed. Only 1 in 5 patients who develop a
serious upper GI adverse event on NSAID therapy is symptomatic.
NSAIDs should be prescribed with extreme caution in those with a prior
history of ulcer disease or gastrointestinal bleeding. Patients with a prior
history of peptic ulcer disease and/or gastrointestinal bleeding who use
NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that
increase the risk for GI bleeding in patients treated with NSAIDs include
concomitant use of oral corticosteroids or anticoagulants, longer duration of
NSAID therapy, smoking, use of alcohol, older age, and poor general health
status. Most spontaneous reports of fatal GI events are in elderly or debilitated
patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with
an NSAID, the lowest effective dose should be used for the shortest possible
duration. Patients and physicians should remain alert for signs and symptoms
of GI ulceration and bleeding during NSAID therapy and promptly initiate
additional evaluation and treatment if a serious GI adverse event is suspected.
This should include discontinuation of the NSAID until a serious GI adverse
event is ruled out. For high risk patients, alternate therapies that do not
involve NSAIDs should be considered.
10
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Epidemiological studies, both of the case-control and cohort design, have
demonstrated an association between use of psychotropic drugs that interfere
with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
In two studies, concurrent use of an NSAID or aspirin potentiated the risk of
bleeding (see PRECAUTIONS: Drug Interactions). Although these studies
focused on upper gastrointestinal bleeding, there is reason to believe that
bleeding at other sites may be similarly potentiated.
NSAIDs should be given with care to patients with a history of inflammatory
bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be
exacerbated.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis
and other renal injury. Renal toxicity has also been seen in patients in whom
renal prostaglandins have a compensatory role in the maintenance of renal
perfusion.
In
these
patients,
administration
of
a
nonsteroidal
anti-inflammatory drug may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, hypovolemia, heart failure,
liver dysfunction, salt depletion, those taking diuretics and angiotensin
converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs),
and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug
therapy is usually followed by recovery to the pretreatment state (see
WARNINGS: Advanced Renal Disease).
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use
of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
NAPROSYN Suspension in patients with advanced renal disease. Therefore,
treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS
and NAPROSYN Suspension is not recommended in these patients with
advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close
monitoring of the patient’s renal function is advisable and patients should be
adequately hydrated.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without
known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX
DS
or
NAPROSYN
Suspension.
NAPROSYN,
EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
should not be given to patients with the aspirin triad. This symptom complex
typically occurs in asthmatic patients who experience rhinitis with or without
11
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
nasal polyps, or who exhibit severe, potentially fatal bronchospasm after
taking aspirin or other NSAIDs (see CONTRAINDICATIONS and
PRECAUTIONS: Preexisting Asthma). Emergency help should be sought
in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like
anaphylaxis, may have a fatal outcome.
Skin Reactions
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse
events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and
toxic epidermal necrolysis (TEN), which can be fatal. These serious events
may occur without warning. Patients should be informed about the signs and
symptoms of serious skin manifestations and use of the drug should be
discontinued at the first appearance of skin rash or any other sign of
hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided
because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
Naproxen-containing products such as NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE, and
other naproxen products should not be used concomitantly since they all
circulate in the plasma as the naproxen anion.
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
NAPROSYN Suspension cannot be expected to substitute for corticosteroids
or to treat corticosteroid insufficiency. Abrupt discontinuation of
corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is
made to discontinue corticosteroids and the patient should be observed closely
for any evidence of adverse effects, including adrenal insufficiency and
exacerbation of symptoms of arthritis.
Patients with initial hemoglobin values of 10 g or less who are to receive long-
term therapy should have hemoglobin values determined periodically.
The
pharmacological
activity
of
NAPROSYN,
EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever
and inflammation may diminish the utility of these diagnostic signs in
detecting complications of presumed noninfectious, noninflammatory painful
conditions.
12
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Because of adverse eye findings in animal studies with drugs of this class, it is
recommended that ophthalmic studies be carried out if any change or
disturbance in vision occurs.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of
patients
taking
NSAIDs
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic
abnormalities may be the result of hypersensitivity rather than direct toxicity.
These laboratory abnormalities may progress, may remain essentially
unchanged, or may be transient with continued therapy. The SGPT (ALT) test
is probably the most sensitive indicator of liver dysfunction. Notable
elevations of ALT or AST (approximately three or more times the upper limit
of normal) have been reported in approximately 1% of patients in clinical
trials with NSAIDs. In addition, rare cases of severe hepatic reactions,
including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic
failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in
whom an abnormal liver test has occurred, should be evaluated for evidence
of the development of more severe hepatic reaction while on therapy with
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
or
NAPROSYN Suspension.
If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension
should be discontinued.
Chronic alcoholic liver disease and probably other diseases with decreased or
abnormal plasma proteins (albumin) reduce the total plasma concentration of
naproxen, but the plasma concentration of unbound naproxen is increased.
Caution is advised when high doses are required and some adjustment of
dosage may be required in these patients. It is prudent to use the lowest
effective dose.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
NAPROSYN Suspension. This may be due to fluid retention, occult or gross
GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension,
should have their hemoglobin or hematocrit checked if they exhibit any signs
or symptoms of anemia.
13
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding
time in some patients. Unlike aspirin, their effect on platelet function is
quantitatively less, of shorter duration, and reversible. Patients receiving either
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
or
NAPROSYN Suspension who may be adversely affected by alterations in
platelet function, such as those with coagulation disorders or patients
receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in
patients with aspirin-sensitive asthma has been associated with severe
bronchospasm, which can be fatal. Since cross reactivity, including
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
should not be administered to patients with this form of aspirin sensitivity and
should be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing
therapy. Patients should also be encouraged to read the NSAID
Medication Guide that accompanies each prescription dispensed.
1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension, like other NSAIDs, may cause serious CV side
effects, such as MI or stroke, which may result in hospitalization and even
death. Although serious CV events can occur without warning symptoms,
patients should be alert for the signs and symptoms of chest pain,
shortness of breath, weakness, slurring of speech, and should ask for
medical advice when observing any indicative sign or symptoms. Patients
should be apprised of the importance of this follow-up (see WARNINGS:
Cardiovascular Effects).
2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort
and, rarely, serious GI side effects, such as ulcers and bleeding, which
may result in hospitalization and even death. Although serious GI tract
ulcerations and bleeding can occur without warning symptoms, patients
should be alert for the signs and symptoms of ulcerations and bleeding,
and should ask for medical advice when observing any indicative sign or
symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
Patients should be apprised of the importance of this follow-up (see
WARNINGS: Gastrointestinal Effects - Risk of Ulceration, Bleeding,
and Perforation).
14
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension, like other NSAIDs, can cause serious skin side
effects such as exfoliative dermatitis, SJS, and TEN, which may result in
hospitalizations and even death. Although serious skin reactions may
occur without warning, patients should be alert for the signs and
symptoms of skin rash and blisters, fever, or other signs of
hypersensitivity such as itching, and should ask for medical advice when
observing any indicative signs or symptoms. Patients should be advised to
stop the drug immediately if they develop any type of rash and contact
their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight
gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of
hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper
quadrant tenderness, and “flu-like” symptoms). If these occur, patients
should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (eg,
difficulty breathing, swelling of the face or throat). If these occur, patients
should be instructed to seek immediate emergency help (see
WARNINGS).
7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be
avoided because it may cause premature closure of the ductus arteriosus.
8. Caution should be exercised by patients whose activities require alertness
if they experience drowsiness, dizziness, vertigo or depression during
therapy with naproxen.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning
symptoms, physicians should monitor for signs or symptoms of GI bleeding.
Patients on long-term treatment with NSAIDs should have their CBC and a
chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur
(eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
NAPROSYN Suspension should be discontinued.
Drug Interactions
Angiotensin Converting Enzyme (ACE)-inhibitors/Angiotensin
Receptor Blockers (ARBs)
NSAIDs may diminish the antihypertensive effect of ACE-inhibitors, ARBs,
or beta-blockers (including propanolol).
Monitor patients taking NSAIDs concomitantly with ACE-inhibitors, ARBs,
or beta blockers for changes in blood pressure.
15
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
In addition, in patients who are elderly, volume-depleted (including those on
diuretic therapy), or have compromised renal function, co-administration of
NSAIDs with ACE inhibitors or ARBs may result in deterioration of renal
function, including possible acute renal failure. Monitor these patients closely
for signs of worsening renal function
Antacids and Sucralfate
Concomitant administration of some antacids (magnesium oxide or aluminum
hydroxide) and sucralfate can delay the absorption of naproxen.
Aspirin
When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS or NAPROSYN Suspension is administered with aspirin, its protein
binding is reduced, although the clearance of free NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is
not altered. The clinical significance of this interaction is not known;
however, as with other NSAIDs, concomitant administration of naproxen and
naproxen sodium and aspirin is not generally recommended because of the
potential of increased adverse effects.
Cholestyramine
As with other NSAIDs, concomitant administration of cholestyramine can
delay the absorption of naproxen.
Diuretics
Clinical studies, as well as postmarketing observations, have shown that
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
NAPROSYN Suspension can reduce the natriuretic effect of furosemide and
thiazides in some patients. This response has been attributed to inhibition of
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
patient should be observed closely for signs of renal failure (see
WARNINGS: Renal Effects), as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction
in renal lithium clearance. The mean minimum lithium concentration
increased 15% and the renal clearance was decreased by approximately 20%.
These effects have been attributed to inhibition of renal prostaglandin
synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium
toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate
accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other
16
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular
secretion of methotrexate in an animal model. This may indicate that they
could enhance the toxicity of methotrexate. Caution should be used when
NSAIDs are administered concomitantly with methotrexate.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that
users of both drugs together have a risk of serious GI bleeding higher than
users of either drug alone. No significant interactions have been observed in
clinical studies with naproxen and coumarin-type anticoagulants. However,
caution is advised since interactions have been seen with other nonsteroidal
agents of this class. The free fraction of warfarin may increase substantially in
some subjects and naproxen interferes with platelet function.
Selective Serotonin Reuptake Inhibitors (SSRIs)
There is an increased risk of gastrointestinal bleeding when selective serotonin
reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be
used when NSAIDs are administered concomitantly with SSRIs.
Other Information Concerning Drug Interactions
Naproxen is highly bound to plasma albumin; it thus has a theoretical
potential for interaction with other albumin-bound drugs such as coumarin-
type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or
sulphonylurea should be observed for adjustment of dose if required.
Probenecid given concurrently increases naproxen anion plasma levels and
extends its plasma half-life significantly.
Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive
antacid therapy, concomitant administration of EC-NAPROSYN is not
recommended.
Drug/Laboratory Test Interaction
Naproxen may decrease platelet aggregation and prolong bleeding time. This
effect should be kept in mind when bleeding times are determined.
The administration of naproxen may result in increased urinary values for 17-
ketogenic steroids because of an interaction between the drug and/or its
metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-
corticosteroid measurements (Porter-Silber test) do not appear to be
artifactually altered, it is suggested that therapy with naproxen be temporarily
discontinued 72 hours before adrenal function tests are performed if the
Porter-Silber test is to be used.
17
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic
acid (5HIAA).
Carcinogenesis
A 2-year study was performed in rats to evaluate the carcinogenic potential of
naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2).
The maximum dose used was 0.28 times the systemic exposure to humans at
the recommended dose. No evidence of tumorigenicity was found.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Reproduction studies have been performed in rats at 20 mg/kg/day
(125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20
mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and
mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic
exposure) with no evidence of impaired fertility or harm to the fetus due to the
drug. However, animal reproduction studies are not always predictive of
human response. There are no adequate and well-controlled studies in
pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS and NAPROSYN Suspension should be used in pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
There is some evidence to suggest that when inhibitors of prostaglandin
synthesis are used to delay preterm labor there is an increased risk of neonatal
complications such as necrotizing enterocolitis, patent ductus arteriosus and
intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay
parturition has been associated with persistent pulmonary hypertension, renal
dysfunction and abnormal prostaglandin E levels in preterm infants. Because
of the known effects of nonsteroidal anti-inflammatory drugs on the fetal
cardiovascular system (closure of ductus arteriosus), use during pregnancy
(particularly late pregnancy) should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit
prostaglandin synthesis, an increased incidence of dystocia, delayed
parturition, and decreased pup survival occurred. Naproxen-containing
products are not recommended in labor and delivery because, through its
prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal
circulation and inhibit uterine contractions, thus increasing the risk of uterine
hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension on labor and delivery in
pregnant women are unknown.
18
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Nursing Mothers
The naproxen anion has been found in the milk of lactating women at a
concentration equivalent to approximately 1% of maximum naproxen
concentration in plasma. Because of the possible adverse effects of
prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be
avoided.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 years have
not been established. Pediatric dosing recommendations for juvenile arthritis
are
based
on
well-controlled
studies
(see
DOSAGE
AND
ADMINISTRATION). There are no adequate effectiveness or dose-response
data for other pediatric conditions, but the experience in juvenile arthritis and
other use experience have established that single doses of 2.5 to 5 mg/kg (as
naproxen suspension, see DOSAGE AND ADMINISTRATION), with total
daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients
over 2 years of age.
Geriatric Use
Studies indicate that although total plasma concentration of naproxen is
unchanged, the unbound plasma fraction of naproxen is increased in the
elderly. Caution is advised when high doses are required and some adjustment
of dosage may be required in elderly patients. As with other drugs used in the
elderly, it is prudent to use the lowest effective dose.
Experience indicates that geriatric patients may be particularly sensitive to
certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or
debilitated patients seem to tolerate peptic ulceration or bleeding less well
when these events do occur. Most spontaneous reports of fatal GI events are in
the geriatric population (see WARNINGS).
Naproxen is known to be substantially excreted by the kidney, and the risk of
toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and it may be useful to
monitor renal function. Geriatric patients may be at a greater risk for the
development of a form of renal toxicity precipitated by reduced prostaglandin
formation during administration of nonsteroidal anti-inflammatory drugs (see
WARNINGS: Renal Effects).
ADVERSE REACTIONS
Adverse reactions reported in controlled clinical trials in 960 patients treated
for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions
in patients treated chronically were reported 2 to 10 times more frequently
than they were in short-term studies in the 962 patients treated for mild to
19
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
moderate pain or for dysmenorrhea. The most frequent complaints reported
related to the gastrointestinal tract.
A clinical study found gastrointestinal reactions to be more frequent and more
severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen
compared
to
those
taking
750
mg
naproxen
(see
CLINICAL
PHARMACOLOGY).
In controlled clinical trials with about 80 pediatric patients and in well-
monitored, open-label studies with about 400 pediatric patients with juvenile
arthritis treated with naproxen, the incidence of rash and prolonged bleeding
times were increased, the incidence of gastrointestinal and central nervous
system reactions were about the same, and the incidence of other reactions
were lower in pediatric patients than in adults.
In patients taking naproxen in clinical trials, the most frequently reported
adverse experiences in approximately 1% to 10% of patients are:
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*,
nausea*, constipation*, diarrhea, dyspepsia, stomatitis
Central
Nervous
System:
headache*,
dizziness*,
drowsiness*,
lightheadedness, vertigo
Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating,
purpura
Special Senses: tinnitus*, visual disturbances, hearing disturbances
Cardiovascular: edema*, palpitations
General: dyspnea*, thirst
*Incidence of reported reaction between 3% and 9%. Those reactions
occurring in less than 3% of the patients are unmarked.
In patients taking NSAIDs, the following adverse experiences have also been
reported in approximately 1% to 10% of patients.
Gastrointestinal
(GI)
Experiences,
including:
flatulence,
gross
bleeding/perforation, GI ulcers (gastric/duodenal), vomiting
General: abnormal renal function, anemia, elevated liver enzymes, increased
bleeding time, rashes
The following are additional adverse experiences reported in <1% of patients
taking naproxen during clinical trials and through postmarketing reports.
Those adverse reactions observed through postmarketing reports are italicized.
20
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual
disorders, pyrexia (chills and fever)
Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary
edema
Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the
elderly), ulceration, perforation and obstruction of the upper or lower
gastrointestinal tract. Esophagitis, stomatitis, hematemesis, pancreatitis,
vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative
colitis, Crohn’s disease).
Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases
have been fatal)
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia,
agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
Metabolic and Nutritional: hyperglycemia, hypoglycemia
Nervous System: inability to concentrate, depression, dream abnormalities,
insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive
dysfunction, convulsions
Respiratory: eosinophilic pneumonitis, asthma
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis,
erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus,
pustular reaction, systemic lupus erythematoses, bullous reactions, including
Stevens-Johnson
syndrome,
photosensitive
dermatitis,
photosensitivity
reactions, including rare cases resembling porphyria cutanea tarda
(pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or
other symptoms suggestive of pseudoporphyria occur, treatment should be
discontinued and the patient monitored.
Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar
optic neuritis, papilledema
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial
nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary
necrosis, raised serum creatinine
Reproduction (female): infertility
In patients taking NSAIDs, the following adverse experiences have also been
reported in <1% of patients.
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite
changes, death
21
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Cardiovascular:
hypertension,
tachycardia,
syncope,
arrhythmia,
hypotension, myocardial infarction
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis,
glossitis, eructation
Hepatobiliary: hepatitis, liver failure
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia,
somnolence, tremors, convulsions, coma, hallucinations
Respiratory: asthma, respiratory depression, pneumonia
Dermatologic: exfoliative dermatitis
Special Senses: blurred vision, conjunctivitis
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
OVERDOSAGE
Symptoms and Signs
Significant naproxen overdosage may be characterized by lethargy, dizziness,
drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion,
nausea, transient alterations in liver function, hypoprothrombinemia, renal
dysfunction,
metabolic
acidosis,
apnea,
disorientation
or
vomiting.
Gastrointestinal bleeding can occur. Hypertension, acute renal failure,
respiratory depression, and coma may occur, but are rare. Anaphylactoid
reactions have been reported with therapeutic ingestion of NSAIDs, and may
occur following an overdose. Because naproxen sodium may be rapidly
absorbed, high and early blood levels should be anticipated. A few patients
have experienced convulsions, but it is not clear whether or not these were
drug-related. It is not known what dose of the drug would be life threatening.
The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110
mg/kg in hamsters, and greater than 1000 mg/kg in dogs.
Treatment
Patients should be managed by symptomatic and supportive care following a
NSAID overdose. There are no specific antidotes. Hemodialysis does not
decrease the plasma concentration of naproxen because of the high degree of
its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1
to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients
seen within 4 hours of ingestion with symptoms or following a large overdose.
Forced diuresis, alkalinization of urine or hemoperfusion may not be useful
due to high protein binding.
22
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and
other treatment options before deciding to use NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension.
Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the
dose and frequency should be adjusted to suit an individual patient’s needs.
Different dose strengths and formulations (ie, tablets, suspension) of the
drug are not necessarily bioequivalent. This difference should be taken
into consideration when changing formulation.
Although
NAPROSYN,
NAPROSYN
Suspension,
EC-NAPROSYN,
ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they
have pharmacokinetic differences that may affect onset of action. Onset of
pain relief can begin within 30 minutes in patients taking naproxen sodium
and within 1 hour in patients taking naproxen. Because EC-NAPROSYN
dissolves in the small intestine rather than in the stomach, the absorption of
the drug is delayed compared to the other naproxen formulations (see
CLINICAL PHARMACOLOGY).
The recommended strategy for initiating therapy is to choose a formulation
and a starting dose likely to be effective for the patient and then adjust the
dosage based on observation of benefit and/or adverse events. A lower dose
should be considered in patients with renal or hepatic impairment or in elderly
patients (see WARNINGS and PRECAUTIONS).
Geriatric Patients
Studies indicate that although total plasma concentration of naproxen is
unchanged, the unbound plasma fraction of naproxen is increased in the
elderly. Caution is advised when high doses are required and some adjustment
of dosage may be required in elderly patients. As with other drugs used in the
elderly, it is prudent to use the lowest effective dose.
Patients With Moderate to Severe Renal Impairment
Naproxen-containing products are not recommended for use in patients with
moderate to severe and severe renal impairment (creatinine clearance <30
mL/min) (see WARNINGS: Renal Effects).
23
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
NAPROSYN
250 mg
or 375 mg
or 500 mg
twice daily
twice daily
twice daily
ANAPROX
275 mg (naproxen 250 mg with 25 mg sodium)
twice daily
ANAPROX DS
550 mg (naproxen 500 mg with 50 mg sodium)
twice daily
NAPROSYN
Suspension
250 mg (10 mL/2 tsp)
or 375 mg (15 mL/3 tsp)
or 500 mg (20 mL/4 tsp)
twice daily
twice daily
twice daily
EC-NAPROSYN
375 mg
or 500 mg
twice daily
twice daily
To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet
should not be broken, crushed or chewed during ingestion. NAPROSYN
Suspension should be shaken gently before use.
During long-term administration, the dose of naproxen may be adjusted up or
down depending on the clinical response of the patient. A lower daily dose
may suffice for long-term administration. The morning and evening doses do
not have to be equal in size and the administration of the drug more frequently
than twice daily is not necessary.
In patients who tolerate lower doses well, the dose may be increased to
naproxen 1500 mg/day for limited periods of up to 6 months when a higher
level of anti-inflammatory/analgesic activity is required. When treating such
patients with naproxen 1500 mg/day, the physician should observe sufficient
increased clinical benefits to offset the potential increased risk. The morning
and evening doses do not have to be equal in size and administration of the
drug more frequently than twice daily does not generally make a difference in
response (see CLINICAL PHARMACOLOGY).
Juvenile Arthritis
The use of NAPROSYN Suspension is recommended for juvenile arthritis in
children 2 years or older because it allows for more flexible dose titration
based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day
produced plasma levels of naproxen similar to those seen in adults taking 500
mg of naproxen (see CLINICAL PHARMACOLOGY).
The recommended total daily dose of naproxen is approximately 10 mg/kg
given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup
marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the
NAPROSYN Suspension. The following table may be used as a guide for
dosing of NAPROSYN Suspension:
24
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Patient’s Weight
Dose
Administered as
13 kg (29 lb)
62.5 mg bid 2.5 mL (1/2 tsp) twice daily
25 kg (55 lb)
125 mg bid 5.0 mL (1 tsp) twice daily
38 kg (84 lb)
187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily
Management of Pain, Primary Dysmenorrhea, and Acute
Tendonitis and Bursitis
The recommended starting dose is 550 mg of naproxen sodium as
ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg
every 6 to 8 hours as required. The initial total daily dose should not exceed
1375 mg of naproxen sodium. Thereafter, the total daily dose should not
exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is
more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the
management of acute painful conditions when prompt onset of pain relief is
desired. NAPROSYN may also be used but EC-NAPROSYN is not
recommended for initial treatment of acute pain because absorption of
naproxen is delayed compared to other naproxen-containing products (see
CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE).
Acute Gout
The recommended starting dose is 750 mg of NAPROSYN followed by 250
mg every 8 hours until the attack has subsided. ANAPROX may also be used
at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-
NAPROSYN is not recommended because of the delay in absorption (see
CLINICAL PHARMACOLOGY).
HOW SUPPLIED
NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR
LE 250 on one side and scored on the other. Packaged in light-resistant bottles
of 100.
100’s (bottle): NDC 0004-6313-01.
375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side.
Packaged in light-resistant bottles of 100.
100’s (bottle): NDC 0004-6314-01.
500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and
scored on the other. Packaged in light-resistant bottles of 100.
100’s (bottle): NDC 0004-6316-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-
resistant containers.
25
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5
mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC
0004-0028-28).
Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F).
Dispense in light-resistant containers. Shake gently before use.
EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex
coated tablets imprinted with NPR EC 375 on one side. Packaged in light-
resistant bottles of 100.
100’s (bottle): NDC 0004-6415-01.
500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side.
Packaged in light-resistant bottles of 100.
100’s (bottle): NDC 0004-6416-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-
resistant containers.
ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped,
engraved with NPS-275 on one side. Packaged in bottles of 100.
100’s (bottle): NDC 0004-6202-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-
shaped, engraved with NPS 550 on one side and scored on both sides.
Packaged in bottles of 100.
100’s (bottle): NDC 0004-6203-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
Revised: March 2013
26
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Medication Guide
for
Non-steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID
medicines.)
What is the most important information I should know about medicines
called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or
stroke that can lead to death. This chance increases:
with longer use of NSAID medicines
in people who have heart disease
NSAID medicines should never be used right before or after a
heart surgery called a “coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach
and intestines at any time during treatment. Ulcers and bleeding:
can happen without warning symptoms
may cause death
The chance of a person getting an ulcer or bleeding increases
with:
taking medicines called “corticosteroids” and
“anticoagulants”
longer use
smoking
drinking alcohol
older age
having poor health
NSAID medicines should only be used:
exactly as prescribed
at the lowest dose possible for your treatment
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
27
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
NSAID medicines are used to treat pain and redness, swelling, and heat
(inflammation) from medical conditions such as:
different types of arthritis
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
if you had an asthma attack, hives, or other allergic reaction with
aspirin or any other NSAID medicine
for pain right before or after heart bypass surgery
Tell your healthcare provider:
about all of your medical conditions.
about all of the medicines you take. NSAIDs and some other
medicines can interact with each other and cause serious side
effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
if you are pregnant. NSAID medicines should not be used by
pregnant women late in their pregnancy.
if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)?
Serious side effects include:
heart attack
stroke
high blood pressure
heart failure from body swelling
(fluid retention)
kidney problems including kidney
failure
bleeding and ulcers in the stomach
and intestine
low red blood cells (anemia)
life-threatening skin reactions
life-threatening allergic reactions
liver problems including liver
failure
asthma attacks in people who have
asthma
Other side effects include:
stomach pain
constipation
diarrhea
gas
heartburn
nausea
vomiting
dizziness
28
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
Get emergency help right away if you have any of the following
symptoms:
shortness of breath or trouble
breathing
chest pain
weakness in one part or side of your
body
slurred speech
swelling of the face or
throat
Stop your NSAID medicine and call your healthcare provider right away
if you have any of the following symptoms:
nausea
more tired or weaker than usual
itching
your skin or eyes look yellow
stomach pain
flu-like symptoms
vomit blood
there is blood in your
bowel movement or it is
black and sticky like tar
unusual weight gain
skin rash or blisters with
fever
swelling of the arms and
legs, hands and feet
These are not all the side effects with NSAID medicines. Talk to your
healthcare provider or pharmacist for more information about NSAID
medicines. Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088 or Genentech at 1-888-835-
2555.
Other information about Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs):
Aspirin is an NSAID medicine but it does not increase the chance of a
heart attack. Aspirin can cause bleeding in the brain, stomach, and
intestines. Aspirin can also cause ulcers in the stomach and intestines.
Some of these NSAID medicines are sold in lower doses without a
prescription (over-the-counter). Talk to your healthcare provider before
using over-the-counter NSAIDs for more than 10 days.
29
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
®
®
tablets), ANAPROX /ANAPROX DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with
misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, LodineXL
Fenoprofen
Nalfon, Nalfon200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with
hydrocodone), Combunox (combined with
oxycodone)
Indomethacin
Indocin, IndocinSR, Indo-Lemmon,
Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, AnaproxDS, EC-Naprosyn,
Naprelan, Naprapac (copackaged with
lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin600
*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC)
NSAID, and is usually used for less than 10 days to treat pain. The OTC
NSAID label warns that long term continuous use may increase the risk of
heart attack or stroke.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Medication Guide Revised: October 2010
All registered trademarks in this document are the property of their respective
owners.
30
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
31
ENT/NNT/AST/NNS_210516_PIMG_2012_01_K
Year Genentech, Inc. All rights reserved.
Reference ID: 3280912
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:38.715495
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017581s111,018164s061,018965s020,020067s018lbl.pdf', 'application_number': 18164, 'submission_type': 'SUPPL ', 'submission_number': 61}
|
11,178
|
EC-NAPROSYN (naproxen delayed-release tablets)
NAPROSYN (naproxen tablets)
ANAPROX/ANAPROX DS (naproxen sodium tablets)
Rx only
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
Cardiovascular Thrombotic Events
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of
serious cardiovascular thrombotic events, including myocardial infarction and
stroke, which can be fatal. This risk may occur early in treatment and may
increase with duration of use (see WARNINGS).
NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS are
contraindicated in the setting of coronary artery bypass graft (CABG) surgery
(see CONTRAINDICATIONS, WARNINGS).
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events
including bleeding, ulceration, and perforation of the stomach or intestines,
which can be fatal. These events can occur at any time during use and without
warning symptoms. Elderly patients and patients with a prior history of peptic
ulcer disease and/or GI bleeding are at greater risk for serious GI events (see
WARNINGS).
DESCRIPTION
Naproxen is a propionic acid derivative related to the arylacetic acid group of
nonsteroidal anti-inflammatory drugs.
The chemical names for naproxen and naproxen sodium are (S)-6-methoxy--methyl-2
naphthaleneacetic acid and (S)-6-methoxy--methyl-2-naphthaleneacetic acid, sodium
salt, respectively. Naproxen and naproxen sodium have the following structures,
respectively: structural formula
Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3.
Naproxen sodium has a molecular weight of 252.23 and a molecular formula of
C14H13NaO3.
Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble,
practically insoluble in water at low pH and freely soluble in water at high pH. The
octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium
is a white to creamy white, crystalline solid, freely soluble in water at neutral pH.
NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of
naproxen, pink tablets containing 375 mg of naproxen and yellow tablets containing 500
Reference ID: 3928112
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
mg of naproxen for oral administration. The inactive ingredients are croscarmellose
sodium, iron oxides, povidone and magnesium stearate.
EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-coated white
tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration.
The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate.
The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate,
sodium hydroxide and purified water. The dissolution of this enteric-coated naproxen
tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below
pH 4.
ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of
naproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue
tablets containing 550 mg of naproxen sodium for oral administration. The inactive
ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The
coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl
methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1
4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain
hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or
Opadry YS-1-4216.
CLINICAL PHARMACOLOGY
Mechanism of Action
Naproxen has analgesic, anti-inflammatory, and antipyretic properties. The sodium salt of
naproxen has been developed as a more rapidly absorbed formulation of naproxen for use
as an analgesic.
The mechanism of action of the naproxen, like that of other NSAIDs, is not completely
understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen
concentrations reached during therapy have produced in vivo effects. Prostaglandins
sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in
animal models. Prostaglandins are mediators of inflammation. Because naproxen is an
inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of
prostaglandins in peripheral tissues.
Pharmacokinetics
Naproxen and naproxen sodium are rapidly and completely absorbed from the
gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms
of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak
concentration (Cmax); however, the products do differ in their pattern of absorption. These
differences between naproxen products are related to both the chemical form of naproxen
used and its formulation. Even with the observed differences in pattern of absorption, the
elimination half-life of naproxen is unchanged across products ranging from 12 to 17
hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of
Reference ID: 3928112
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
naproxen accumulation is consistent with this half-life. This suggests that the differences
in pattern of release play only a negligible role in the attainment of steady-state plasma
levels.
Absorption
NAPROSYN
After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4
hours. After oral administration of ANAPROX, peak plasma levels are attained in 1 to 2
hours. The difference in rates between the two products is due to the increased aqueous
solubility of the sodium salt of naproxen used in ANAPROX. Peak plasma levels of
naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours.
EC-NAPROSYN
EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to
disintegration in the acidic environment of the stomach and to lose integrity in the more
neutral environment of the small intestine. The enteric polymer coating selected for EC
NAPROSYN dissolves above pH 6. When EC-NAPROSYN was given to fasted subjects,
peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to
12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN tablets
demonstrated that EC-NAPROSYN dissolves primarily in the small intestine rather than
in the stomach, so the absorption of the drug is delayed until the stomach is emptied.
When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a
crossover study following 1 week of dosing, differences in time to peak plasma levels
(Tmax) were observed, but there were no differences in total absorption as measured by
Cmax and AUC:
EC-NAPROSYN*
NAPROSYN*
500 mg bid
500 mg bid
Cmax (µg/mL)
94.9 (18%)
97.4 (13%)
Tmax (hours)
4 (39%)
1.9 (61%)
AUC0–12 hr (µg·hr/mL)
845 (20%)
767 (15%)
*Mean value (coefficient of variation)
Antacid Effects
When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering
capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was
reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not
significantly (see PRECAUTIONS; Drug Interactions).
Food Effects
When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most
subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the
small intestine until disintegration was independent of food intake. The presence of food
prolonged the time the tablets remained in the stomach, time to first detectable serum
Reference ID: 3928112
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak
naproxen levels (Cmax).
Distribution
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is
greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is
less than proportional increase in plasma levels due to an increase in clearance caused by
saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and
56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The
naproxen anion has been found in the milk of lactating women at a concentration
equivalent to approximately 1% of maximum naproxen concentration in plasma (see
PRECAUTIONS; Nursing Mothers).
Elimination
Metabolism
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both
parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0
desmethyl naproxen are further metabolized to their respective acylglucuronide
conjugated metabolites.
Excretion
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from
any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen
(<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in
humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen’s
metabolites and conjugates are shorter than 12 hours, and their rates of excretion have
been found to coincide closely with the rate of naproxen disappearance from the plasma.
Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients
with renal failure metabolites may accumulate (see WARNINGS; Renal Toxicity and
Hyperkalemia)).
Special Populations
Pediatric Patients
In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a
5
mg/kg
single
dose
of
naproxen
suspension
(see
DOSAGE
AND
ADMINISTRATION) were found to be similar to those found in normal adults
following a 500 mg dose. The terminal half-life appears to be similar in pediatric and
adult patients. Pharmacokinetic studies of naproxen were not performed in pediatric
patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar
following administration of naproxen suspension or tablets in pediatric patients. EC
NAPROSYN has not been studied in subjects under the age of 18.
Geriatric Patients
Studies indicate that although total plasma concentration of naproxen is unchanged, the
unbound plasma fraction of naproxen is increased in the elderly, although the unbound
Reference ID: 3928112
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
fraction is <1% of the total naproxen concentration. Unbound trough naproxen
concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of
total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The
clinical significance of this finding is unclear, although it is possible that the increase in
free naproxen concentration could be associated with an increase in the rate of adverse
events per a given dosage in some elderly patients.
Race
Pharmacokinetic differences due to race have not been studied.
Hepatic Impairment
Naproxen pharmacokinetics has not been determined in subjects with hepatic
insufficiency.
Chronic alcoholic liver disease and probably other diseases with decreased or abnormal
plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the
plasma concentration of unbound naproxen is increased. Caution is advised when high
doses are required and some adjustment of dosage may be required in these patients. It is
prudent to use the lowest effective dose.
Renal Impairment
Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency.
Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney,
the potential exists for naproxen metabolites to accumulate in the presence of renal
insufficiency. Elimination of naproxen is decreased in patients with severe renal
impairment. Naproxen-containing products are not recommended for use in patients with
moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see
WARNINGS; Renal Toxicity and Hyperkalemia).
Drug Interaction Studies
Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs
were reduced, although the clearance of free NSAID was not altered. The clinical
significance of this interaction is not known. See Table 1 for clinically significant drug
interactions of NSAIDs with aspirin (see PRECAUTIONS; Drug Interactions).
CLINICAL STUDIES
General Information
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile
arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in
patients treated for rheumatoid arthritis was demonstrated by a reduction in joint
swelling, a reduction in duration of morning stiffness, a reduction in disease activity as
assessed by both the investigator and patient, and by increased mobility as demonstrated
by a reduction in walking time. Generally, response to naproxen has not been found to be
dependent on age, sex, severity or duration of rheumatoid arthritis.
Reference ID: 3928112
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a
reduction in joint pain or tenderness, an increase in range of motion in knee joints,
increased mobility as demonstrated by a reduction in walking time, and improvement in
capacity to perform activities of daily living impaired by the disease.
In a clinical trial comparing standard formulations of naproxen 375 mg twice a day (750
mg a day) vs 750 mg twice a day (1500 mg/day), 9 patients in the 750 mg group
terminated prematurely because of adverse events. Nineteen patients in the 1500 mg
group terminated prematurely because of adverse events. Most of these adverse events
were gastrointestinal events.
In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile
arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in
controlling the aforementioned measures of disease activity, but the frequency and
severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and
nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in
naproxen-treated patients than in those treated with aspirin or indomethacin.
In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain,
morning stiffness and pain at rest. In double-blind studies the drug was shown to be as
effective as aspirin, but with fewer side effects.
In patients with acute gout, a favorable response to naproxen was shown by significant
clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours,
as well as by relief of pain and tenderness.
Naproxen has been studied in patients with mild to moderate pain secondary to
postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and
dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen
and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown
by such measures as reduction of pain intensity scores, increase in pain relief scores,
decrease in numbers of patients requiring additional analgesic medication, and delay in
time to remedication. The analgesic effect has been found to last for up to 12 hours.
Naproxen may be used safely in combination with gold salts and/or corticosteroids;
however, in controlled clinical trials, when added to the regimen of patients receiving
corticosteroids, it did not appear to cause greater improvement over that seen with
corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been
adequately studied. When added to the regimen of patients receiving gold salts, naproxen
did result in greater improvement. Its use in combination with salicylates is not
recommended because there is evidence that aspirin increases the rate of excretion of
naproxen and data are inadequate to demonstrate that naproxen and aspirin produce
greater improvement over that achieved with aspirin alone. In addition, as with other
NSAIDs, the combination may result in higher frequency of adverse events than
demonstrated for either product alone.
In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of
1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX
Reference ID: 3928112
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
(naproxen sodium) has been demonstrated to cause statistically significantly less gastric
bleeding and erosion than 3250 mg of aspirin.
Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375
or 500 mg twice a day, n=385) and NAPROSYN (375 or 500 mg twice a day, n=279)
were conducted comparing EC-NAPROSYN with NAPROSYN, including 355
rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID-related
GI symptoms. These studies indicated that EC-NAPROSYN and NAPROSYN showed
no significant differences in efficacy or safety and had similar prevalence of minor GI
complaints. Individual patients, however, may find one formulation preferable to the
other.
Five hundred and fifty-three patients received EC-NAPROSYN during long-term open-
label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed
peptic ulcers and GI bleeds were similar to what has been historically reported for long-
term NSAID use.
Geriatric Patients
The hepatic and renal tolerability of long-term naproxen administration was studied in
two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients
were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was
administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months.
Transient abnormalities of laboratory tests assessing hepatic and renal function were
noted in some patients, although there were no differences noted in the occurrence of
abnormal values among different age groups.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN,
ANAPROX or ANAPROX DS and other treatment options before deciding to use
NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS. Use the lowest
effective dosage for the shortest duration consistent with individual patient treatment
goals (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation).
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS is
indicated:
For the relief of the signs and symptoms of rheumatoid arthritis
For the relief of the signs and symptoms of osteoarthritis
For the relief of the signs and symptoms of ankylosing spondylitis
For the relief of the signs and symptoms of juvenile arthritis
Naproxen as naproxen suspension is recommended for juvenile rheumatoid arthritis in
order to obtain the maximum dosage flexibility based on the patient’s weight.
Naproxen as NAPROSYN, ANAPROX and ANAPROX DS and is also indicated:
Reference ID: 3928112
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
For relief of the signs and symptoms of tendonitis
For relief of the signs and symptoms of bursitis
For relief of the signs and symptoms of acute gout
For the management of pain
For the management of primary dysmenorrhea
EC-NAPROSYN is not recommended for initial treatment of acute pain because the
absorption of naproxen is delayed compared to absorption from other naproxen-
containing
products
(see
CLINICAL
PHARMACOLOGY,
DOSAGE
AND
ADMINISTRATION).
CONTRAINDICATIONS
NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS are contraindicated in
the following patients:
Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to
naproxen, naproxen sodium, or any components of the drug product (see
WARNINGS; Anaphylactic Reactions, Serious Skin Reactions).
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or
other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have
been reported in such patients (see WARNINGS; Anaphylactic Reactions,
Exacerbation of Asthma Related to Aspirin Sensitivity).
In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS;
Cardiovascular Thrombotic Events).
WARNINGS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years
duration have shown an increased risk of serious cardiovascular (CV) thrombotic events,
including myocardial infarction (MI) and stroke, which can be fatal. Based on available
data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The
relative increase in serious CV thrombotic events over baseline conferred by NSAID use
appears to be similar in those with and without known CV disease or risk factors for CV
disease. However, patients with known CV disease or risk factors had a higher absolute
incidence of excess serious CV thrombotic events, due to their increased baseline rate.
Some observational studies found that this increased risk of serious CV thrombotic events
began as early as the first weeks of treatment. The increase in CV thrombotic risk has
been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use
the lowest effective dose for the shortest duration possible. Physicians and patients
Reference ID: 3928112
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
should remain alert for the development of such events, throughout the entire treatment
course, even in the absence of previous CV symptoms. Patients should be informed about
the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk
of serious CV thrombotic events associated with NSAID use. The concurrent use of
aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal
(GI) events (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of
pain in the first 10-14 days following CABG surgery found an increased incidence of
myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG
(see CONTRAINDICATIONS).
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that
patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction,
CV-related death, and all-cause mortality beginning in the first week of treatment. In this
same cohort, the incidence of death in the first year post-MI was 20 per 100 person years
in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed
patients. Although the absolute rate of death declined somewhat after the first year post-
MI, the increased relative risk of death in NSAID users persisted over at least the next
four years of follow-up.
Avoid the use of NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS in
patients with a recent MI unless the benefits are expected to outweigh the risk of
recurrent CV thrombotic events. If NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS is used in patients with a recent MI, monitor patients for signs of cardiac
ischemia.
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including naproxen cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small
intestine, or large intestine, which can be fatal. These serious adverse events can occur at
any time, with or without warning symptoms, in patients treated with NSAIDs. Only one
in five patients who develop a serious upper GI adverse event on NSAID therapy is
symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs
occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of
patients treated for one year. However, even short-term NSAID therapy is not without
risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs
had a greater than 10-fold increased risk for developing a GI bleed compared to patients
without these risk factors. Other factors that increase the risk of GI bleeding in patients
Reference ID: 3928112
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral
corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs);
smoking; use of alcohol; older age; and poor general health status. Most postmarketing
reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients
with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the
increased risk of bleeding. For such patients, as well as those with active GI
bleeding, consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during
NSAID therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and
treatment, and discontinue NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis,
monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS;
Drug Interactions).
Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have
been reported in approximately 1% of patients in clinical trials. In addition, rare,
sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver
necrosis and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of
patients taking NSAIDs including naproxen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu
like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or
if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPROSYN,
EC-NAPROSYN, ANAPROX or ANAPROX DS immediately, and perform a clinical
evaluation of the patient.
Hypertension
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS,
can lead to new onset of hypertension or worsening of preexisting hypertension, either of
which may contribute to the increased incidence of CV events. Patients taking
angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may
have impaired response to these therapies when taking NSAIDs (see PRECAUTIONS;
Drug Interactions).
Reference ID: 3928112
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the
course of therapy.
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized
controlled trials demonstrated an approximately two-fold increase in hospitalization for
heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients
compared to placebo-treated patients. In a Danish National Registry study of patients
with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure,
and death.
Additionally, fluid retention and edema have been observed in some patients treated with
NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to
treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor
blockers [ARBs]) (see PRECAUTIONS; Drug Interactions).
Avoid the use of NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS in
patients with severe heart failure unless the benefits are expected to outweigh the risk of
worsening heart failure. If NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX
DS is used in patients with severe heart failure, monitor patients for signs of worsening
heart failure.
Since each ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium
(about 1 mEq per each 250 mg of naproxen), this should be considered in patients whose
overall intake of sodium must be severely restricted.
Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other
renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In these patients, administration
of an NSAID may cause a dose-dependent reduction in prostaglandin formation and,
secondarily, in renal blood flow, which may precipitate overt renal decompensation.
Patients at greatest risk of this reaction are those with impaired renal function,
dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and
ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually
followed by recovery to the pretreatment state
No information is available from controlled clinical studies regarding the use of
NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS in patients with
advanced renal disease. The renal effects of NAPROSYN, EC-NAPROSYN, ANAPROX
or ANAPROX DS may hasten the progression of renal dysfunction in patients with
preexisting renal disease.
Reference ID: 3928112
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Correct volume status in dehydrated or hypovolemic patients prior to initiating
NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS. Monitor renal function
in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia
during use of NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS (see
PRECAUTIONS; Drug Interactions). Avoid the use of NAPROSYN, EC-NAPROSYN,
ANAPROX or ANAPROX DS in patients with advanced renal disease unless the benefits
are expected to outweigh the risk of worsening renal function. If NAPROSYN, EC
NAPROSYN, ANAPROX or ANAPROX DS is used in patients with advanced renal
disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported
with use of NSAIDs, even in some patients without renal impairment. In patients with
normal renal function, these effects have been attributed to a hyporeninemic
hypoaldosteronism state.
Anaphylactic Reactions
Naproxen has been associated with anaphylactic reactions in patients with and without
known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma (see
CONTRAINDICATIONS, WARNINGS; Exacerbation of Asthma Related to Aspirin
Sensitivity).
Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may
include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal
bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity
between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients,
NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS are contraindicated in
patients with this form of aspirin sensitivity (see CONTRAINDICATIONS). When
NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS are used in patients
with preexisting asthma (without known aspirin sensitivity), monitor patients for changes
in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN),
which can be fatal. These serious events may occur without warning. Inform patients
about the signs and symptoms of serious skin reactions and to discontinue the use of
NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS at the first appearance
of skin rash or any other sign of hypersensitivity. NAPROSYN, EC-NAPROSYN,
ANAPROX and ANAPROX DS are contraindicated in patients with previous serious
skin reactions to NSAIDs (see CONTRAINDICATIONS).
Reference ID: 3928112
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Premature Closure of Fetal Ductus Arteriosus
Naproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS, in
pregnant women starting at 30 weeks of gestation (third trimester) (see PRECAUTIONS;
Pregnancy).
Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross
blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a
patient treated with NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS has
any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS,
may increase the risk of bleeding events. Co-morbid conditions such as coagulation
disorders, or concomitant use of warfarin and other anticoagulants, antiplatelet agents
(e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine
reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of
bleeding (see PRECAUTIONS; Drug Interactions).
PRECAUTIONS
General
Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX and
ANAPROX DS, and other naproxen products should not be used concomitantly since
they all circulate in the plasma as the naproxen anion.
NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS cannot be expected to
substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt
discontinuation of corticosteroids may lead to disease exacerbation. Patients on
prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is
made to discontinue corticosteroids and the patient should be observed closely for any
evidence of adverse effects, including adrenal insufficiency and exacerbation of
symptoms of arthritis.
Patients with initial hemoglobin values of 10g or less who are to receive long-term
therapy should have hemoglobin values determined periodically.
Because of adverse eye findings in animal studies with drugs of this class, it is
recommended that ophthalmic studies be carried out if any change or disturbance in
vision occurs.
Information for Patients
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that
accompanies each prescription dispensed. Inform patients, families, or their caregivers of
Reference ID: 3928112
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
the following information before initiating therapy with NAPROSYN, EC-NAPROSYN,
ANAPROX or ANAPROX DS and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events,
including chest pain, shortness of breath, weakness, or slurring of speech, and to report
any of these symptoms to their health care provider immediately (see WARNINGS;
Cardiovascular Thrombotic Events).
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain,
dyspepsia, melena, and hematemesis to their health care provider. In the setting of
concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the
increased risk for the signs and symptoms of GI bleeding (see WARNINGS;
Gastrointestinal Bleeding, Ulceration, and Perforation).
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like”
symptoms). If these occur, instruct patients to stop NAPROSYN, EC-NAPROSYN,
ANAPROX or ANAPROX DS and seek immediate medical therapy (see WARNINGS;
Hepatotoxicity).
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including
shortness of breath, unexplained weight gain, or edema and to contact their healthcare
provider if such symptoms occur (see WARNINGS; Heart Failure and Edema).
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing,
swelling of the face or throat). Instruct patients to seek immediate emergency help if
these occur (see CONTRAINDICATION, WARNINGS; Anaphylactic Reactions).
Serious Skin Reactions
Advise patients to stop NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS
immediately if they develop any type of rash and to contact their healthcare provider as
soon as possible (see WARNINGS; Serious Skin Reactions).
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including
VOLTAREN, may be associated with a reversible delay in ovulation (see
PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility).
Fetal Toxicity
Inform pregnant women to avoid use of NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and other NSAIDs starting at 30 weeks gestation because of the risk of
Reference ID: 3928112
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
the premature closing of the fetal ductus arteriosus (see WARNINGS; Premature Closure
of Fetal Ductus Arteriosus).
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX
and ANAPROX DS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not
recommended due to the increased risk of gastrointestinal toxicity, and little or no
increase in efficacy (see WARNINGS;: Gastrointestinal Bleeding, Ulceration, and
Perforation, PRECAUTIONS; Drug Interactions). Alert patients that NSAIDs may be
present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with NAPROSYN, EC
NAPROSYN, ANAPROX and ANAPROX DS until they talk to their healthcare provider
(see PRECAUTIONS; Drug Interactions).
Activities Requiring Alertness
Caution should be exercised by patients whose activities require alertness if they
experience drowsiness, dizziness, vertigo or depression during therapy with naproxen.
Masking of Inflammation and Fever
The pharmacological activity of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS in reducing inflammation, and possibly fever, may diminish the utility of
diagnostic signs in detecting infections.
Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning
symptoms or signs, consider monitoring patients on long-term NSAID treatment with a
CBC and a chemistry profile periodically (see WARNINGS; Gastrointestinal Bleeding,
Ulceration and Perforation, and Hepatotoxicity).
.
Drug Interactions
See Table 1 for clinically significant drug interactions with naproxen.
Table 1: Clinically Significant Drug Interactions with naproxen
Drugs That Interfere with Hemostasis
Clinical Impact:
• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding.
The concomitant use of naproxen and anticoagulants has an increased risk of serious
bleeding compared to the use of either drug alone.
• Serotonin release by platelets plays an important role in hemostasis. Case-control
and cohort epidemiological studies showed that concomitant use of drugs that
interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding
Reference ID: 3928112
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
more than an NSAID alone.
Intervention:
Monitor patients with concomitant use of NAPROSYN, EC-NAPROSYN,
ANAPROX or ANAPROX DS with anticoagulants (e.g., warfarin), antiplatelet
agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin
norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS;
Hematologic Toxicity).
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic
doses of aspirin does not produce any greater therapeutic effect than the use of
NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was
associated with a significantly increased incidence of GI adverse reactions as
compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding,
Ulceration and Perforation).
Intervention:
Concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS
and analgesic doses of aspirin is not generally recommended because of the increased
risk of bleeding (see WARNINGS; Hematologic Toxicity).
NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS is not a substitute
for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
• NSAIDs may diminish the antihypertensive effect of angiotensin converting
enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers
(including propranolol).
• In patients who are elderly, volume-depleted (including those on diuretic therapy),
or have renal impairment, co-administration of an NSAID with ACE inhibitors or
ARBs may result in deterioration of renal function, including possible acute renal
failure. These effects are usually reversible.
Intervention:
• During concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure
to ensure that the desired blood pressure is obtained.
• During concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS and ACE-inhibitors or ARBs in patients who are elderly, volume-
depleted, or have impaired renal function, monitor for signs of worsening renal
function (see WARNINGS; Renal Toxicity and Hyperkalemia).
When these drugs are administered concomitantly, patients should be adequately
hydrated. Assess renal function at the beginning of the concomitant treatment and
periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs
reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide
diuretics in some patients. This effect has been attributed to the NSAID inhibition of
renal prostaglandin synthesis.
Intervention
During concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS with diuretics, observe patients for signs of worsening renal function,
in addition to assuring diuretic efficacy including antihypertensive effects (see
Reference ID: 3928112
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:
The concomitant use of naproxen with digoxin has been reported to increase the
serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal
lithium clearance. The mean minimum lithium concentration increased 15%, and the
renal clearance decreased by approximately 20%. This effect has been attributed to
NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate
toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS
and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS and cyclosporine, monitor patients for signs of worsening renal
function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal,
salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see
WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:
The concomitant use of naproxen with other NSAIDs or salicylates is not
recommended.
Pemetrexed
Clinical Impact:
Concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or ANAPROX DS
and pemetrexed may increase the risk of pemetrexed-associated myelosuppression,
renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
During concomitant use of NAPROSYN, EC-NAPROSYN, ANAPROX or
ANAPROX DS and pemetrexed, in patients with renal impairment whose creatinine
clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI
toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be
avoided for a period of two days before, the day of, and two days following
administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and
Reference ID: 3928112
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these
NSAIDs should interrupt dosing for at least five days before, the day of, and two days
following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:
Concomitant administration of some antacids (magnesium oxide or aluminum
hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:
Concomitant administration of antacids such as magnesium oxide or aluminum
hydroxide, and sucralfate with NAPROSYN EC-NAPROSYN, ANAPROX or
ANAPROX DS is not recommended.
Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive
antacid therapy, concomitant administration of EC-NAPROSYN is not
recommended.
Cholestyramine
Clinical Impact:
Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:
Concomitant administration of cholestyramine with NAPROSYN EC-NAPROSYN,
ANAPROX or ANAPROX DS is not recommended.
Probenecid
Clinical Impact:
Probenecid given concurrently increases naproxen anion plasma levels and extends
its plasma half-life significantly.
Intervention:
Patients simultaneously receiving NAPROSYN EC-NAPROSYN, ANAPROX or
ANAPROX DS and probenecid should be observed for adjustment of dose if
required.
Other albumin-bound drugs
Clinical Impact:
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for
interaction with other albumin-bound drugs such as coumarin-type anticoagulants,
sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:
Patients simultaneously receiving NAPROSYN EC-NAPROSYN, ANAPROX or
ANAPROX DS and a hydantoin, sulphonamide or sulphonylurea should be observed
for adjustment of dose if required.
Drug/Laboratory Test Interactions
Bleeding times
Clinical Impact:
Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:
This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:
The administration of naproxen may result in increased urinary values for 17
ketogenic steroids because of an interaction between the drug and/or its metabolites
with m-di-nitrobenzene used in this assay.
Intervention:
Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear
to be artifactually altered, it is suggested that therapy with naproxen be temporarily
discontinued 72 hours before adrenal function tests are performed if the Porter-Silber
test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid
Reference ID: 3928112
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
(5HIAA).
Intervention:
This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is
determined.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen
at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum
recommended human daily dose [MRHD] of 1500 mg/day based on a body surface area
comparison). No evidence of tumorigenicity was found.
Mutagenesis
Studies to evaluate the mutagenic potential of Naprosyn, EC-Naprosyn, Anaprox or
Anaprox DS tablets have not been completed.
Impairment of fertility
Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days
prior to mating and female rats were treated with the same doses for 14 days prior to
mating and for the first 7 days of pregnancy. There were no adverse effects on fertility
noted (up to 0.13 times the MRDH based on body surface area).
Pregnancy
Risk Summary
Use of NSAIDs, including Naprosyn, EC-Naprosyn, Anaprox, and Anaprox DS tablets,
during the third trimester of pregnancy increases the risk of premature closure of the fetal
ductus arteriosus. Avoid use of NSAIDs, including Naprosyn, in pregnant women starting
at 30 weeks of gestation (third trimester) (see WARNINGS; Premature Closure of Fetal
Ductus Arteriosus).
There are no adequate and well-controlled studies of Naprosyn, EC-Naprosyn, Anaprox,
or Anaprox DS tablets in pregnant women.
Data from observational studies regarding potential embryofetal risks of NSAID use in
women in the first or second trimesters of pregnancy are inconclusive. In the general
U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have
a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In
animal reproduction studies in rats, rabbit, and mice no evidence of teratogenicity or fetal
harm when naproxen was administered during the period of organogenesis at doses 0.13,
0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day,
respectively.
Based on animal data, prostaglandins have been shown to have an
important role in endometrial vascular permeability, blastocyst implantation, and
decidualization. In animal studies, administration of prostaglandin synthesis inhibitors
such as naproxen, resulted in increased pre- and post-implantation loss.
Reference ID: 3928112
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Data
Human Data
There is some evidence to suggest that when inhibitors of prostaglandin synthesis are
used to delay preterm labor there is an increased risk of neonatal complications such as
necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen
treatment given in late pregnancy to delay parturition has been associated with persistent
pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in
preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on
the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy
(particularly starting at 30-weeks of gestation, or third trimester) should be avoided.
Animal Data
Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the
maximum recommended human daily dose of 1500 mg/day based on body surface area
comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human
daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6
times the maximum recommended human daily dose based on body surface area
comparison) with no evidence of impaired fertility or harm to the fetus due to the drug.
Based on animal data, prostaglandins have been shown to have an important role in
endometrial vascular permeability, blastocyst implantation, and decidualization. In
animal studies, administration of prostaglandin synthesis inhibitors such as naproxen,
resulted in increased pre- and post-implantation loss.
Labor and Delivery
There are no studies on the effects of Naprosyn, EC-Naprosyn, Anaprox, or Anaprox DS
tablets during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit
prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Nursing Mothers
The naproxen anion has been found in the milk of lactating women at a concentration
equivalent to approximately 1% of maximum naproxen concentration in plasma. The
developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for Naprosyn, EC-Naprosyn, Anaprox, or Anaprox DS tablets and
any potential adverse effects on the breastfed infant from the Naprosyn, EC-Naprosyn,
Anaprox, or Anaprox DS tablets or from the underlying maternal condition.
Females and Males of Reproductive Potential
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs,
including Naprosyn, may delay or prevent rupture of ovarian follicles, which has
been associated with reversible infertility in some women. Published animal studies
have shown that administration of prostaglandin synthesis inhibitors has the
potential to disrupt prostaglandin- mediated follicular rupture required for
ovulation. Small studies in women treated with NSAIDs have also shown a
reversible delay in ovulation.
Reference ID: 3928112
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Consider withdrawal of NSAIDs, including Naprosyn, EC-Naprosyn, Anaprox and
Anaprox DS tablets, in women who have difficulties conceiving or who are
undergoing investigation of infertility.
Pediatric Use
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 years have not been
established. Pediatric dosing recommendations for juvenile arthritis are based on well-
controlled studies (see DOSAGE AND ADMINISTRATION). There are no adequate
effectiveness or dose-response data for other pediatric conditions, but the experience in
juvenile arthritis and other use experience have established that single doses of 2.5 to 5
mg/kg (as naproxen suspension, see DOSAGE AND ADMINISTRATION), with total
daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2
years of age. Safety and effectiveness in pediatric patients below the age of 2 years have
not been established.
Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-
associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If
the anticipated benefit for the elderly patient outweighs these potential risks, start
dosing at the low end of the dosing range, and monitor patients for adverse effects
(see WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding,
Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia,
PRECAUTIONS; Laboratory Monitoring ).
Studies indicate that although total plasma concentration of naproxen is unchanged, the
unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when
high doses are required and some adjustment of dosage may be required in elderly
patients. As with other drugs used in the elderly, it is prudent to use the lowest effective
dose.
Experience indicates that geriatric patients may be particularly sensitive to certain
adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients
seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most
spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS;
Gastrointestinal Bleeding, Ulceration, and Perforation).
Naproxen is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function. Geriatric patients may be
at a greater risk for the development of a form of renal toxicity precipitated by reduced
prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs
(see WARNINGS: Renal Toxicity and Hyperkalemia).
Reference ID: 3928112
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling:
•
Cardiovascular Thrombotic Events (see WARNINGS)
•
GI Bleeding, Ulceration and Perforation (see WARNINGS)
•
Hepatotoxicity (see WARNINGS)
•
Hypertension (see WARNINGS)
•
Heart Failure and Edema (see WARNINGS)
•
Renal Toxicity and Hyperkalemia (see WARNINGS)
•
Anaphylactic Reactions (see WARNINGS)
•
Serious Skin Reactions (see WARNINGS)
•
Hematologic Toxicity (see WARNINGS)
Adverse reactions reported in controlled clinical trials in 960 patients treated for
rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients
treated chronically were reported 2 to 10 times more frequently than they were in short-
term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea.
The most frequent complaints reported related to the gastrointestinal tract.
A clinical study found gastrointestinal reactions to be more frequent and more severe in
rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those
taking 750 mg naproxen (see CLINICAL PHARMACOLOGY).
In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-
label studies with about 400 pediatric patients with juvenile arthritis treated with
naproxen, the incidence of rash and prolonged bleeding times were increased, the
incidence of gastrointestinal and central nervous system reactions were about the same,
and the incidence of other reactions were lower in pediatric patients than in adults.
In patients taking naproxen in clinical trials, the most frequently reported adverse
experiences in approximately 1% to 10% of patients are:
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*, nausea*,
constipation*, diarrhea, dyspepsia, stomatitis
Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo
Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating, purpura
Special Senses: tinnitus*, visual disturbances, hearing disturbances
Cardiovascular: edema*, palpitations
General: dyspnea*, thirst
*Incidence of reported reaction between 3% and 9%. Those reactions occurring in less
than 3% of the patients are unmarked.
Reference ID: 3928112
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
In patients taking NSAIDs, the following adverse experiences have also been reported in
approximately 1% to 10% of patients.
Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI
ulcers (gastric/duodenal), vomiting
General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding
time, rashes
The following are additional adverse experiences reported in <1% of patients taking
naproxen during clinical trials and through postmarketing reports. Those adverse
reactions observed through postmarketing reports are italicized.
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders,
pyrexia (chills and fever)
Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema
Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly),
ulceration, perforation and obstruction of the upper or lower gastrointestinal tract.
Esophagitis, stomatitis, hematemesis, pancreatitis, vomiting, colitis, exacerbation of
inflammatory bowel disease (ulcerative colitis, Crohn’s disease).
Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been
fatal)
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia,
agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
Metabolic and Nutritional: hyperglycemia, hypoglycemia
Nervous System: inability to concentrate, depression, dream abnormalities, insomnia,
malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction,
convulsions
Respiratory: eosinophilic pneumonitis, asthma
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema
multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction,
systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome,
photosensitive dermatitis, photosensitivity reactions, including rare cases resembling
porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility,
blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be
discontinued and the patient monitored.
Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic
neuritis, papilledema
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis,
nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum
creatinine
Reference ID: 3928112
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Reproduction (female): infertility
In patients taking NSAIDs, the following adverse experiences have also been reported in
<1% of patients.
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death
Cardiovascular:
hypertension,
tachycardia,
syncope,
arrhythmia,
hypotension,
myocardial infarction
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis,
eructation
Hepatobiliary: hepatitis, liver failure
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence,
tremors, convulsions, coma, hallucinations
Respiratory: asthma, respiratory depression, pneumonia
Dermatologic: exfoliative dermatitis
Special Senses: blurred vision, conjunctivitis
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
OVERDOSAGE
Symptoms following acute NSAID overdosages have been typically limited to
lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been
generally reversible with supportive care. Gastrointestinal bleeding has occurred.
Hypertension, acute renal failure, respiratory depression, and coma have occurred,
but were rare. Because naproxen sodium may be rapidly absorbed, high and early
blood levels should be anticipated. A few patients have experienced convulsions,
but it is not clear whether or not these were drug-related. It is not known what dose
of the drug would be life threatening. (see WARNINGS; Cardiovascular
Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation,
Hypertension, Renal Toxicity and Hyperkalemia).
Manage patients with symptomatic and supportive care following an NSAID overdosage.
There are no specific antidotes. Hemodialysis does not decrease the plasma concentration
of naproxen because of the high degree of its protein binding. Consider emesis and/or
activated charcoal (60 to 100 g in adults, 1 to 2 g/kg of body weight in pediatric patients)
and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in
patients with a large overdosage (5 to 10 times the recommended dosage). Forced
Reference ID: 3928112
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to
high protein binding.
For additional information about overdosage treatment contact a poison control center
(1-800-222-1222).
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN,
ANAPROX and ANAPROX DS and other treatment options before deciding to use
NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS. Use the lowest
effective dose for the shortest duration consistent with individual patient treatment goals
(see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).
After observing the response to initial therapy with NAPROSYN, EC-NAPROSYN,
ANAPROX or ANAPROX DS, the dose and frequency should be adjusted to suit an
individual patient’s needs.
Different dose strengths and formulations (i.e., tablets, suspension) of the drug are
not necessarily bioequivalent. This difference should be taken into consideration
when changing formulation.
Although NAPROSYN, EC-NAPROSYN, ANAPROX and ANAPROX DS all circulate
in the plasma as naproxen, they have pharmacokinetic differences that may affect onset
of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen
sodium and within 1 hour in patients taking naproxen. Because EC-NAPROSYN
dissolves in the small intestine rather than in the stomach, the absorption of the drug is
delayed
compared
to
the
other
naproxen
formulations
(see
CLINICAL
PHARMACOLOGY).
The recommended strategy for initiating therapy is to choose a formulation and a starting
dose likely to be effective for the patient and then adjust the dosage based on observation
of benefit and/or adverse events. A lower dose should be considered in patients with renal
or hepatic impairment or in elderly patients (see WARNINGS; Hepatotoxicity, and Renal
Toxicity and Hyperkalemia, and PRECAUTIONS; Geriatric Use).
Geriatric Patients
Studies indicate that although total plasma concentration of naproxen is unchanged, the
unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when
high doses are required and some adjustment of dosage may be required in elderly
patients. As with other drugs used in the elderly, it is prudent to use the lowest effective
dose.
Patients With Moderate to Severe Renal Impairment
Naproxen-containing products are not recommended for use in patients with moderate to
severe and severe renal impairment (creatinine clearance <30 mL/min) (see
WARNINGS: Renal Effects).
Reference ID: 3928112
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
NAPROSYN
250 mg
or 375 mg
or 500 mg
twice daily
twice daily
twice daily
ANAPROX
275 mg (naproxen 250 mg with 25 mg sodium)
twice daily
ANAPROX DS
550 mg (naproxen 500 mg with 50 mg sodium)
twice daily
EC-NAPROSYN
375 mg
or 500 mg
twice daily
twice daily
To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be
broken, crushed or chewed during ingestion.
During long-term administration, the dose of naproxen may be adjusted up or down
depending on the clinical response of the patient. A lower daily dose may suffice for
long-term administration. The morning and evening doses do not have to be equal in size
and the administration of the drug more frequently than twice daily is not necessary.
In patients who tolerate lower doses well, the dose may be increased to naproxen 1500
mg/day for limited periods of up to 6 months when a higher level of anti
inflammatory/analgesic activity is required. When treating such patients with naproxen
1500 mg/day, the physician should observe sufficient increased clinical benefits to offset
the potential increased risk. The morning and evening doses do not have to be equal in
size and administration of the drug more frequently than twice daily does not generally
make a difference in response (see CLINICAL PHARMACOLOGY).
Juvenile Arthritis
Naprosyn Tablets may not allow for the flexible dose titration needed in pediatric patients
with juvenile arthritis. A liquid formulation may be more appropriate.
In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to
those seen in adults taking 500 mg of naproxen (see Clinical Pharmacology).
The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2
divided doses. One-half of the 250 mg tablet will be needed for dosing lower-weight
children. Dosing with Naprosyn Tablets is not appropriate for children weighing less
than 25 kilograms.
The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2
divided doses (i.e., 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon
and 2.5 milliliter increments is provided with the naproxen suspension. The following
table may be used as a guide for dosing of naproxen suspension:
Reference ID: 3928112
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Patient’s Weight
Dose
Administered as
13 kg (29 lb)
62.5 mg bid 2.5 mL (1/2 tsp) twice daily
25 kg (55 lb)
125 mg bid 5.0 mL (1 tsp) twice daily
38 kg (84 lb)
187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily
Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and
Bursitis
The
recommended
starting
dose
is
550
mg
of
naproxen
sodium
as
ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8
hours as required. The initial total daily dose should not exceed 1375 mg of naproxen
sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium.
Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX/ANAPROX
DS is recommended for the management of acute painful conditions when prompt onset
of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not
recommended for initial treatment of acute pain because absorption of naproxen is
delayed
compared
to
other
naproxen-containing
products
(see
CLINICAL
PHARMACOLOGY, INDICATIONS AND USAGE).
Acute Gout
The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8
hours until the attack has subsided. ANAPROX may also be used at a starting dose of
825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended
because of the delay in absorption (see CLINICAL PHARMACOLOGY).
HOW SUPPLIED
NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on
one side and scored on the other. Packaged in light-resistant bottles of 100.
100’s (bottle): NDC 0004-6313-01.
375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-
resistant bottles of 100.
100’s (bottle): NDC 0004-6314-01.
500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on
the other. Packaged in light-resistant bottles of 100.
100’s (bottle): NDC 69437-316-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant
containers.
EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex coated
tablets imprinted with NPR EC 375 on one side. Packaged in light-resistant bottles of
100.
Reference ID: 3928112
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
100’s (bottle): NDC 69437-415-01.
500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side. Packaged
in light-resistant bottles of 100.
100’s (bottle): NDC 69437-416-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant
containers.
ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with
NPS-275 on one side. Packaged in bottles of 100.
100’s (bottle): NDC 0004-6202-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-shaped, engraved
with NPS 550 on one side and scored on both sides. Packaged in bottles of 100.
100’s (bottle): NDC 69437-203-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
Manufactured for:
Atnahs Pharma US Ltd
Miles Gray Road,
Basildon Essex SS14 3FR
United Kingdom
Distributed by:
Canton Laboratories, LLC
Alpharetta, GA 30004-5945
United States
Reference ID: 3928112
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
Medication Guide for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAIDs can cause serious side effects, including:
Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in
treatment and may increase:
o with increasing doses of NSAIDs
o with longer use of NSAIDs
Do not take NSAIDs right before or after a heart surgery called a “coronary artery
bypass graft (CABG).” Avoid taking NSAIDs after a recent heart attack, unless your
healthcare provider tells you to. You may have an increased risk of another heart
attack if you take NSAIDs after a recent heart attack.
Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading
from the mouth to the stomach), stomach and intestines:
o any time during use
o without warning symptoms
o that may cause death
The risk of getting an ulcer or bleeding increases with:
o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
o increasing doses of NSAIDs
o longer use of NSAIDs
o smoking
o drinking alcohol
o older age
o poor health
o advanced liver disease
o bleeding problems
NSAIDs should only be used:
o exactly as prescribed
o at the lowest dose possible for your treatment
o for the shortest time needed
What are NSAIDs?
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as different types of arthritis, menstrual cramps, and other types of short-
term pain.
Who should not take NSAIDs?
Do not take NSAIDs:
•
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other
NSAIDs.
•
right before or after heart bypass surgery.
Before taking NSAIDs, tell your healthcare provider about all of your medical
conditions, including if you:
•
have liver or kidney problems
•
have high blood pressure
•
have asthma
•
are pregnant or plan to become pregnant. Talk to your healthcare provider if you are
considering taking NSAIDs during pregnancy. You should not take NSAIDs after
Reference ID: 3928112
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
29 weeks of pregnancy.
•
are breastfeeding or plan to breastfeed.
Tell your healthcare provider about all of the medicines you take, including
prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs
and some other medicines can interact with each other and cause serious side effects. Do not
start taking any new medicine without talking to your healthcare provider first.
What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:
See “What is the most important information I should know about medicines called
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?
• new or worse high blood pressure
• heart failure
• liver problems including liver failure
• kidney problems including kidney failure
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas,
heartburn, nausea, vomiting, and dizziness.
Get emergency help right away if you have any of the following symptoms:
shortness of breath or trouble breathing
chest pain
weakness in one part or side of your body
slurred speech
swelling of the face or throat
Stop taking your NSAID and call your healthcare provider right away if you get any of
the following symptoms:
nausea
•
vomit blood
more tired or weaker than usual
diarrhea
itching
•
there is blood in your bowel
movement or it is black and sticky
like tar
your skin or eyes look yellow
indigestion or stomach pain
flu-like symptoms
•
unusual weight gain
•
skin rash or blisters with fever
•
swelling of the arms and legs,
hands and feet
If you take too much of your NSAID, call your healthcare provider or get medical help
right away.
These are not all the possible side effects of NSAIDs. For more information, ask your
healthcare provider or pharmacist about NSAIDs.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
Other information about NSAIDs
•
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack.
Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also
cause ulcers in the stomach and intestines.
Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your
Reference ID: 3928112
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
healthcare provider before using over-the-counter NSAIDs for more than 10 days.
General information about the safe and effective use of NSAIDs
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give
NSAIDs to other people, even if they have the same symptoms that you have. It may harm
them.
If you would like more information about NSAIDs, talk with your healthcare provider. You
can ask your pharmacist or healthcare provider for information about NSAIDs that is written
for health professionals.
Manufactured for:
Atnahs Pharma US Ltd
Miles Gray Road,
Basildon Essex SS14 3FR
United Kingdom
Distributed by:
Canton Laboratories, LLC
Alpharetta, GA 30004-5945
United States
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: Month 2016
All registered trademarks in this document are the property of their respective owners.
Reference ID: 3928112
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:38.835326
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017581s112,018164s062,020067s019lbl.pdf', 'application_number': 18164, 'submission_type': 'SUPPL ', 'submission_number': 62}
|
11,179
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
INDOCIN® SR safely and effectively. See full prescribing information for
INDOCIN SR.
INDOCIN SR (indomethacin) extended-release capsules for oral use
Initial U.S. Approval: 1965
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
See full prescribing information for complete boxed warning.
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased
risk of serious cardiovascular thrombotic events, including myocardial
infarction and stroke, which can be fatal. This risk may occur early in
treatment and may increase with duration of use (5.1)
INDOCIN SR is contraindicated in the setting of coronary artery
bypass graft (CABG) surgery (4, 5.1)
NSAIDs cause an increased risk of serious gastrointestinal (GI)
adverse events including bleeding, ulceration, and perforation of the
stomach or intestines, which can be fatal. These events can occur at
any time during use and without warning symptoms. Elderly patients
and patients with a prior history of peptic ulcer disease and/or GI
bleeding are at greater risk for serious GI events (5.2)
RECENT MAJOR CHANGES
Boxed Warning
5/2016
Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016
Warnings and Precautions, Heart Failure and Edema (5.5)
5/2016
INDICATIONS AND USAGE
INDOCIN SR is a nonsteroidal anti-inflammatory drug indicated for:
Moderate to severe rheumatoid arthritis including acute flares of chronic
disease
Moderate to severe ankylosing spondylitis
Moderate to severe osteoarthritis
Acute painful shoulder (bursitis and/or tendinitis) (1)
DOSAGE AND ADMINISTRATION
Use the lowest effective dosage for shortest duration consistent with
individual patient treatment goals (2.1)
The dosage for moderate to severe rheumatoid arthritis including acute
flares of chronic disease; moderate to severe ankylosing spondylitis; and
moderate to severe osteoarthritis is one INDOCIN SR 75 mg capsule daily
(2.2)
The dosage for acute painful shoulder (bursitis and/or tendinitis) is one
INDOCIN SR 75 mg capsule once or twice daily (2.3)
DOSAGE FORMS AND STRENGTHS
INDOCIN SR (indomethacin) extended-releasde capsules: 75 mg (3)
CONTRAINDICATIONS
Known hypersensitivity to indomethacin or any components of the drug
product (4)
History of asthma, urticaria, or other allergic-type reactions after taking
aspirin or other NSAIDs (4)
In the setting of CABG surgery (4)
WARNINGS AND PRECAUTIONS
Hepatotoxicity: Inform patients of warning signs and symptoms of
hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if
clinical signs and symptoms of liver disease develop (5.3)
Hypertension: Patients taking some antihypertensive medications may have
impaired response to these therapies when taking NSAIDs. Monitor blood
pressure (5.4, 7)
Heart Failure and Edema: Avoid use of INDOCIN SR in patients with
severe heart failure unless benefits are expected to outweigh risk of
worsening heart failure (5.5)
Renal Toxicity: Monitor renal function in patients with renal or hepatic
impairment, heart failure, dehydration, or hypovolemia. Avoid use of
INDOCIN SR in patients with advanced renal disease unless benefits are
expected to outweigh risk of worsening renal function (5.6)
Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction
occurs (5.7)
Exacerbation of Asthma Related to Aspirin Sensitivity: INDOCIN SR is
contraindicated in patients with aspirin-sensitive asthma. Monitor patients
with preexisting asthma (without aspirin sensitivity) (5.8)
Serious Skin Reactions: Discontinue INDOCIN SR at first appearance of
skin rash or other signs of hypersensitivity (5.9)
Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant
women starting at 30 weeks gestation (5.10, 8.1)
Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with
any signs or symptoms of anemia (5.11, 7)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥ 3%) are headache, dizziness,
dyspepsia and nausea. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Iroko
Pharmaceuticals, LLC at 1-877-757-0676 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
DRUG INTERACTIONS
Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs):
Monitor patients for bleeding who are concomitantly taking INDOCIN SR
with drugs that interfere with hemostasis. Concomitant use of INDOCIN
SR and analgesic doses of aspirin is not generally recommended (7)
ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers:
Concomitant use with INDOCIN SR may diminish the antihypertensive
effect of these drugs. Monitor blood pressure (7)
ACE Inhibitors and ARBs: Concomitant use with INDOCIN SR in elderly,
volume depleted, or those with renal impairment may result in deterioration
of renal function. In such high risk patients, monitor for signs of worsening
renal function (7)
Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide
diuretics. Monitor patients to assure diuretic efficacy including
antihypertensive effects (7)
Digoxin: Concomitant use with INDOCIN SR can increase serum
concentration and prolong half-life of digoxin. Monitor serum digoxin
levels (7)
USE IN SPECIFIC POPULATIONS
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases
the risk of premature closure of the fetal ductus arteriosus. Avoid use of
NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1)
Infertility: NSAIDs are associated with reversible infertility. Consider
withdrawal of INDOCIN SR in women who have difficulties conceiving (8.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised 5/2016
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Instructions
2.2
Moderate to severe rheumatoid arthritis including acute
flares of chronic disease; moderate to severe ankylosing
spondylitis; and moderate to severe osteoarthritis
2.3
Acute painful shoulder (bursitis and/or tendinitis)
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Cardiovascular Thrombotic Events
5.2
Gastrointestinal Bleeding, Ulceration, and Perforation
5.3
Hepatotoxicity
5.4
Hypertension
5.5
Heart Failure and Edema
5.6
Renal Toxicity and Hyperkalemia
5.7
Anaphylactic Reactions
5.8
Exacerbation of Asthma Related to Aspirin Sensitivity
5.9
Serious Skin Reactions
5.10
Premature Closure of Fetal Ductus Arteriosus
5.11
Hematologic Toxicity
5.12
Masking of Inflammation and Fever
5.13
Laboratory Monitoring
5.14
Central Nervous System Effects
5.15
Ocular Effects
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
Cardiovascular Thrombotic Events
• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious
cardiovascular thrombotic events, including myocardial infarction and stroke,
which can be fatal. This risk may occur early in treatment and may increase with
duration of use [see Warnings and Precautions (5.1)].
• INDOCIN SR is contraindicated in the setting of coronary artery bypass graft
(CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events
including bleeding, ulceration, and perforation of the stomach or intestines, which
can be fatal. These events can occur at any time during use and without warning
symptoms. Elderly patients and patients with a prior history of peptic ulcer disease
and/or GI bleeding are at greater risk for serious GI events [see Warnings and
Precautions (5.2)].
1
INDICATIONS AND USAGE
INDOCIN SR is indicated for:
Moderate to severe rheumatoid arthritis including acute flares of chronic disease
Moderate to severe ankylosing spondylitis
Moderate to severe osteoarthritis
Acute painful shoulder (bursitis and/or tendinitis)
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Instructions
Carefully consider the potential benefits and risks of INDOCIN SR and other treatment
options before deciding to use INDOCIN SR. Use the lowest effective dosage for the shortest
duration consistent with individual patient treatment goals [see Warnings and Precautions
(5)].
After observing the response to initial therapy with indomethacin, the dose and frequency
should be adjusted to suit an individual patient’s needs.
Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore,
every effort should be made to determine the lowest effective dosage for the individual
patient.
THIS SECTION PREDOMINANTLY REFERENCES THE INDOMETHACIN
IMMEDIATE-RELEASE CAPSULE ORAL DOSAGE AND IS INTENDED TO PROVIDE
GUIDANCE IN USING INDOCIN SR EXTENDED-RELEASE CAPSULES, 75 MG
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN SR, 75 mg once a day can be substituted for indomethacin immediate-release
capsules, 25 mg three times a day. However, there will be significant differences
between the two dosage regimens in indomethacin blood levels, especially after 12 hours
[see Clinical Pharmacology (12)]. In addition, INDOCIN SR, 75 mg twice a day can be
substituted for indomethacin immediate-release capsules, USP 50 mg three times a day.
INDOCIN SR may be substituted for all the indications for indomethacin immediate-
release capsules, USP except acute gouty arthritis.
Dosage Recommendations for Active Stages of the Following:
2.2 Moderate to severe rheumatoid arthritis including acute flares of
chronic disease; moderate to severe ankylosing spondylitis; and
moderate to severe osteoarthritis
Indomethacin immediate-release capsules, 25 mg twice a day or three times a day. If this is
well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing
symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily
dose of 150 - 200 mg is reached. Doses above this amount generally do not increase the
effectiveness of the drug.
In patients who have persistent night pain and/or morning stiffness, the giving of a large
portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in
affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic
rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by
50 mg daily.
If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a
tolerated dose and observe the patient closely.
If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under
control, an attempt to reduce the daily dose should be made repeatedly until the patient is
receiving the smallest effective dose or the drug is discontinued.
Careful instructions to, and observations of, the individual patient are essential to the
prevention of serious, irreversible, including fatal, adverse reactions.
As advancing years appear to increase the possibility of adverse reactions, INDOCIN SR
should be used with greater care in the elderly [see Use in Specific Populations (8.5)].
2.3 Acute painful shoulder (bursitis and/or tendinitis)
Indomethacin immediate-release capsules 75-150 mg daily in 3 or 4 divided doses.
Discontinue INDOCIN SR treatment after the signs and symptoms of inflammation have
been controlled for several days. The usual course of therapy is 7-14 days.
3 DOSAGE FORMS AND STRENGTHS
INDOCIN SR (indomethacin) extended-release capsules 75 mg - opaque blue cap and clear
body hard shell gelatin capsules, containing a mixture of blue and white pellets, printed with
both 157 and WPPh.
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
CONTRAINDICATIONS
INDOCIN SR is contraindicated in the following patients:
Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to
indomethacin or any components of the drug product [see Warnings and Precautions
(5.7, 5.9)]
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other
NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported
in such patients [see Warnings and Precautions (5.7, 5.8)]
In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and
Precautions (5.1)]
5
WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years
duration have shown an increased risk of serious cardiovascular (CV) thrombotic events,
including myocardial infarction (MI) and stroke, which can be fatal. Based on available data,
it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative
increase in serious CV thrombotic events over baseline conferred by NSAID use appears to
be similar in those with and without known CV disease or risk factors for CV disease.
However, patients with known CV disease or risk factors had a higher absolute incidence of
excess serious CV thrombotic events, due to their increased baseline rate. Some observational
studies found that this increased risk of serious CV thrombotic events began as early as the
first weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the
lowest effective dose for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, throughout the entire treatment course, even in the
absence of previous CV symptoms. Patients should be informed about the symptoms of
serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of
serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and
an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events
[see Warnings and Precautions (5.2)].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in
the first 10–14 days following CABG surgery found an increased incidence of myocardial
infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see
Contraindications (4)].
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that
patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction,
CV-related death, and all-cause mortality beginning in the first week of treatment. In this
same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in
NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed
patients. Although the absolute rate of death declined somewhat after the first year post-MI,
the increased relative risk of death in NSAID users persisted over at least the next four years
of follow-up.
Avoid the use of INDOCIN SR in patients with a recent MI unless the benefits are expected
to outweigh the risk of recurrent CV thrombotic events. If INDOCIN SR is used in patients
with a recent MI, monitor patients for signs of cardiac ischemia.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach,
small intestine, or large intestine, which can be fatal. These serious adverse events can occur
at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one
in five patients who develop a serious upper GI adverse event on NSAID therapy is
symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in
approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated
for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had
a greater than 10-fold increased risk for developing a GI bleed compared to patients without
these risk factors. Other factors that increase the risk of GI bleeding in patients treated with
NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids,
aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of
alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI
events occurred in elderly or debilitated patients. Additionally, patients with advanced liver
disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the
increased risk of bleeding. For such patients, as well as those with active GI bleeding,
consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID
therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment,
and discontinue INDOCIN SR until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor
patients more closely for evidence of GI bleeding [see Drug Interactions (7)].
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5.3 Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been
reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare,
sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis,
and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients
treated with NSAIDs including indomethacin.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like"
symptoms). If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue INDOCIN SR
immediately, and perform a clinical evaluation of the patient.
5.4 Hypertension
NSAIDs, including INDOCIN SR, can lead to new onset of hypertension or worsening of
preexisting hypertension, either of which may contribute to the increased incidence of CV
events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or
loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug
Interactions (7)].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the
course of therapy.
5.5 Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized
controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart
failure in COX-2 selective-treated patients and nonselective NSAID-treated patients
compared to placebo-treated patients. In a Danish National Registry study of patients with
heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with
NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to
treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor
blockers [ARBs]) [see Drug Interactions (7)].
Avoid the use of INDOCIN SR in patients with severe heart failure unless the benefits are
expected to outweigh the risk of worsening heart failure. If INDOCIN SR is used in patients
with severe heart failure, monitor patients for signs of worsening heart failure.
5.6 Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal
injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In these patients, administration of
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an NSAID may cause a dose-dependent reduction in prostaglandin formation and,
secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients
at greatest risk of this reaction are those with impaired renal function, dehydration,
hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or
ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to
the pretreatment state.
No information is available from controlled clinical studies regarding the use of INDOCIN
SR in patients with advanced renal disease. The renal effects of INDOCIN SR may hasten the
progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN
SR. Monitor renal function in patients with renal or hepatic impairment, heart failure,
dehydration, or hypovolemia during use of INDOCIN SR [see Drug Interactions (7)]. Avoid
the use of INDOCIN SR in patients with advanced renal disease unless the benefits are
expected to outweigh the risk of worsening renal function. If INDOCIN SR is used in patients
with advanced renal disease, monitor patients for signs of worsening renal function.
It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a
maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four
healthy volunteers. Indomethacin and triamterene should not be administered together.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with
use of NSAIDs, even in some patients without renal impairment. In patients with normal
renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism
state.
Both Indomethacin and potassium-sparing diuretics may be associated with increased serum
potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on
potassium levels and renal function should be considered when these agents are administered
concurrently.
5.7 Anaphylactic Reactions
Indomethacin has been associated with anaphylactic reactions in patients with and without
known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see
Contraindications (4) and Warnings and Precautions (5.8)].
Seek emergency help if an anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may
include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal
bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity
between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients,
INDOCIN SR is contraindicated in patients with this form of aspirin sensitivity [see
Contraindications (4)]. When INDOCIN SR is used in patients with preexisting asthma
(without known aspirin sensitivity), monitor patients for changes in the signs and symptoms
of asthma.
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5.9 Serious Skin Reactions
NSAIDs, including indomethacin, can cause serious skin adverse reactions such as
exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis
(TEN), which can be fatal. These serious events may occur without warning. Inform patients
about the signs and symptoms of serious skin reactions, and to discontinue the use of
INDOCIN SR at the first appearance of skin rash or any other sign of hypersensitivity.
INDOCIN SR is contraindicated in patients with previous serious skin reactions to NSAIDs
[see Contraindications (4)].
5.10 Premature Closure of Fetal Ductus Arteriosus
Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of
NSAIDs, including INDOCIN SR, in pregnant women starting at 30 weeks of gestation (third
trimester) [see Use in Specific Populations (8.1)].
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood
loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated
with INDOCIN SR has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including INDOCIN SR, may increase the risk of bleeding events. Co-morbid
conditions, such as coagulation disorders, or concomitant use of warfarin, other
anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and
serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these
patients for signs of bleeding [see Drug Interactions (7)].
5.12 Masking of Inflammation and Fever
The pharmacological activity of INDOCIN SR in reducing inflammation, and possibly fever,
may diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning
symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC
and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].
5.14 Central Nervous System Effects
INDOCIN SR may aggravate depression or other psychiatric disturbances, epilepsy, and
parkinsonism, and should be used with considerable caution in patients with these conditions.
Discontinue INDOCIN SR if severe CNS adverse reactions develop.
INDOCIN SR may cause drowsiness; therefore, caution patients about engaging in activities
requiring mental alertness and motor coordination, such as driving a car. Indomethacin may
also cause headache. Headache which persists despite dosage reduction requires cessation of
therapy with INDOCIN SR.
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5.15 Ocular Effects
Corneal deposits and retinal disturbances, including those of the macula, have been observed
in some patients who had received prolonged therapy with INDOCIN SR. Be alert to the
possible association between the changes noted and INDOCIN SR. It is advisable to
discontinue therapy if such changes are observed. Blurred vision may be a significant
symptom and warrants a thorough ophthalmological examination. Since these changes may
be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients
receiving prolonged therapy. INDOCIN SR is not indicated for long-term treatment.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling:
Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
Hepatotoxicity [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Heart Failure and Edema [see Warnings and Precautions (5.5)]
Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
Anaphylactic Reactions [see Warnings and Precautions (5.7)]
Serious Skin Reactions [see Warnings and Precautions (5.9)]
Hematologic Toxicity [see Warnings and Precautions (5.11)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in clinical practice.
In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities
was significantly higher in the group receiving indomethacin immediate-release capsules
than in the group taking indomethacin suppositories or placebo.
In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis,
however, the incidence of upper gastrointestinal adverse effects with indomethacin
immediate-release capsules or suppositories was comparable. The incidence of lower
gastrointestinal adverse effects was greater in the suppository group.
The adverse reactions for indomethacin immediate-release capsules listed in the following
table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence
less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled
clinical trials reported in the literature (1,092 patients). The incidence for group (2) was
based on reports in clinical trials, in the literature, and on voluntary reports since marketing.
The probability of a causal relationship exists between INDOCIN and these adverse
reactions, some of which have been reported only rarely.
The adverse reactions reported with indomethacin immediate-release capsules may occur
with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in
patients who have received the capsules.
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Table 1
Summary of Adverse Reactions for INDOCIN Capsules
Incidence greater than 1%
Incidence less than 1%
GASTROINTESTINAL
nausea * with or
without vomiting
dyspepsia * (including
indigestion, heartburn and
epigastric pain)
diarrhea
abdominal distress or pain
constipation
anorexia
bloating (includes distension)
flatulence
peptic ulcer
gastroenteritis
rectal bleeding
proctitis
single or multiple ulcerations,
including perforation and hemorrhage
of the esophagus, stomach,
duodenum or small and large
intestines
intestinal ulceration associated with
stenosis and obstruction
gastrointestinal bleeding without
obvious ulcer formation and
perforation of preexisting
sigmoid lesions (diverticulum,
carcinoma, etc.) development
of ulcerative colitis and
regional ileitis
ulcerative stomatitis
toxic hepatitis and jaundice
(some fatal cases have been
reported)
intestinal strictures
(diaphragms)
CENTRAL NERVOUS SYSTEM
headache (11.7%)
dizziness *
vertigo
somnolence
depression and fatigue
(including malaise and
listlessness)
anxiety (includes nervousness)
muscle weakness
involuntary muscle movements
insomnia
muzziness
psychic disturbances including
psychotic episodes
mental confusion
drowsiness
light-headedness
syncope
paresthesia
aggravation of epilepsy and
parkinsonism
depersonalization
coma
peripheral neuropathy
convulsion
dysarthria
SPECIAL SENSES
tinnitus
ocular — corneal deposits and retinal
disturbances, including those of
the macula, have been reported in
some patients on prolonged therapy with
INDOCIN
blurred vision
diplopia
hearing disturbances, deafness
CARDIOVASCULAR
None
hypertension
hypotension
tachycardia
chest pain
congestive heart failure
arrhythmia; palpitations
METABOLIC
None
edema
weight gain
fluid retention
flushing or sweating
hyperglycemia
glycosuria
hyperkalemia
INTEGUMENTARY
none
pruritus
rash; urticaria
petechiae or ecchymosis
exfoliative dermatitis
erythema nodosum
loss of hair
Stevens-Johnson syndrome
erythema multiforme
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Incidence greater than 1%
Incidence less than 1%
toxic epidermal necrolysis
HEMATOLOGIC
None
leukopenia
bone marrow depression
anemia secondary to obvious or occult
gastrointestinal bleeding
aplastic anemia
hemolytic anemia
agranulocytosis
thrombocytopenic purpura
disseminated intravascular
coagulation
HYPERSENSITIVITY
None
acute anaphylaxis
acute respiratory distress
rapid fall in blood pressure resembling
a shock-like state
angioedema
dyspnea
asthma
purpura
angiitis
pulmonary edema
fever
GENITOURINARY
None
hematuria
vaginal bleeding
proteinuria
nephrotic syndrome
interstitial nephritis
BUN elevation
renal insufficiency, including renal
failure
MISCELLANEOUS
None
epistaxis
breast changes, including enlargement
and tenderness, or gynecomastia
* Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than 3% of the
patients are unmarked.)
Causal relationship unknown: Other reactions have been reported but occurred under
circumstances where a causal relationship could not be established. However, in these rarely
reported events, the possibility cannot be excluded. Therefore, these observations are being
listed to serve as alerting information to physicians:
Cardiovascular: Thrombophlebitis
Hematologic: Although there have been several reports of leukemia, the supporting
information is weak
Genitourinary: Urinary frequency
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with
Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal
anti-inflammatory agents, including indomethacin, sometimes with fatal outcome.
7
DRUG INTERACTIONS
See Table 2 for clinically significant drug interactions with indomethacin.
Table 2
Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact:
Indomethacin and anticoagulants such as warfarin have a synergistic effect on
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bleeding. The concomitant use of indomethacin and anticoagulants have an increased
risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and
cohort epidemiological studies showed that concomitant use of drugs that interfere
with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than
an NSAID alone.
Intervention:
Monitor patients with concomitant use of INDOCIN SR with anticoagulants (e.g.,
warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors
(SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding
[see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic
doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs
alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated
with a significantly increased incidence of GI adverse reactions as compared to use of
the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:
Concomitant use of INDOCIN SR and analgesic doses of aspirin is not generally
recommended because of the increased risk of bleeding [see Warnings and Precautions
(5.11)].
INDOCIN SR is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme
(ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including
propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or
have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs
may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Intervention:
During concomitant use of INDOCIN SR and ACE-inhibitors, ARBs, or beta-
blockers, monitor blood pressure to ensure that the desired blood pressure is
obtained.
During concomitant use of INDOCIN SR and ACE-inhibitors or ARBs in patients
who are elderly, volume-depleted, or have impaired renal function, monitor for signs
of worsening renal function [see Warnings and Precautions (5.6)].
When these drugs are administered concomitantly, patients should be adequately
hydrated. Assess renal function at the beginning of the concomitant treatment and
periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced
the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some
patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin
synthesis.
It has been reported that the addition of triamterene to a maintenance schedule of
INDOCIN SR resulted in reversible acute renal failure in two of four healthy
volunteers. INDOCIN SR and triamterene should not be administered together.
Both INDOCIN SR and potassium-sparing diuretics may be associated with increased
serum potassium levels. The potential effects of INDOCIN SR and potassium-sparing
diuretics on potassium levels and renal function should be considered when these agents
are administered concurrently.
Intervention:
Indomethacin and triamterene should not be administered together.
During concomitant use of INDOCIN SR with diuretics, observe patients for signs of
worsening renal function, in addition to assuring diuretic efficacy including
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antihypertensive effects.
Be aware that indomethacin and potassium-sparing diuretics may both be associated
with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:
The concomitant use of indomethacin with digoxin has been reported to increase the
serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of INDOCIN SR and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal
lithium clearance. The mean minimum lithium concentration increased 15%, and the
renal clearance decreased by approximately 20%. This effect has been attributed to
NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of INDOCIN SR and lithium, monitor patients for signs of
lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate
toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of INDOCIN SR and methotrexate, monitor patients for
methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of INDOCIN SR and cyclosporine may increase cyclosporine’s
nephrotoxicity.
Intervention:
During concomitant use of INDOCIN SR and cyclosporine, monitor patients for signs
of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal,
salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see
Warnings and Precautions (5.2)].
Combined use with diflunisal may be particularly hazardous because diflunisal causes
significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)].
In some patients, combined use of indomethacin and diflunisal has been associated with
fatal gastrointestinal hemorrhage.
Intervention:
The concomitant use of indomethacin with other NSAIDs or salicylates, especially
diflunisal, is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of INDOCIN SR and pemetrexed may increase the risk of
pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed
prescribing information).
Intervention:
During concomitant use of INDOCIN SR and pemetrexed, in patients with renal
impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for
myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be
avoided for a period of two days before, the day of, and two days following
administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs
with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs
should interrupt dosing for at least five days before, the day of, and two days following
pemetrexed administration.
Probenecid
Clinical Impact:
When indomethacin is given to patients receiving probenecid, the plasma levels of
indomethacin are likely to be increased.
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Intervention:
During the concomitant use of INDOCIN SR and probenecid, a lower total daily dosage
of indomethacin may produce a satisfactory therapeutic effect. When increases in the
dose of indomethacin are made, they should be made carefully and in small increments.
Effects on Laboratory Tests
Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced
by furosemide administration, or salt or volume depletion. These facts should be considered when
evaluating plasma renin activity in hypertensive patients.
False-negative results in the dexamethasone suppression test (DST) in patients being treated
with indomethacin have been reported. Thus, results of the DST should be interpreted with
caution in these patients.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Use of NSAIDs, including INDOCIN SR, during the third trimester of pregnancy increases
the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including
INDOCIN SR, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of INDOCIN SR in pregnant women.
Data from observational studies regarding potential embryofetal risks of NSAID use in
women in the first or second trimesters of pregnancy are inconclusive. In the general U.S.
population, all clinically recognized pregnancies, regardless of drug exposure, have a
background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal
reproduction studies retarded fetal ossification was observed with administration of
indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively,
the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant
mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and
fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the
last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1
and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins
have been shown to have an important role in endometrial vascular permeability, blastocyst
implantation, and decidualization. In animal studies, administration of prostaglandin
synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation
loss.
Clinical Considerations
Labor or Delivery
There are no studies on the effects of INDOCIN SR during labor or delivery. In animal
studies, NSAIDs, including indomethacin, inhibit prostaglandin synthesis, cause delayed
parturition, and increase the incidence of stillbirth.
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Data
Animal data
Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and
4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and
0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the
decreased average fetal weights, no increase in fetal malformations was observed as
compared with control groups. Other studies in mice reported in the literature using higher
doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal
toxicity and death, increased fetal resorptions, and fetal malformations.
In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1
times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an
increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however
no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control
groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0
mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal
necrosis at either dose level.
8.2 Lactation
Risk Summary
Based on available published clinical data, indomethacin may be present in human milk. The
developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for INDOCIN SR and any potential adverse effects on the breastfed
infant from the INDOCIN SR or from the underlying maternal condition.
Data
In one study, levels of indomethacin in breast milk were below the sensitivity of the assay
(<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally
daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average
concentration present in breast milk was estimated to be 0.27% of the maternal weight-
adjusted dose. In another study indomethacin levels were measured in breast milk of eight
postpartum women using doses of 75 mg daily and the results were used to calculate an
estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was
less than 30 mcg/day or 4.5 mcg/ kg/day assuming breast milk intake of 150 mL/kg/day.
This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for
treatment of patent ductus arteriosus.
8.3 Females and Males of Reproductive Potential
Infertility
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including
INDOCIN SR, may delay or prevent rupture of ovarian follicles, which has been associated
with reversible infertility in some women. Published animal studies have shown that
administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-
mediated follicular rupture required for ovulation. Small studies in women treated with
NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs,
including INDOCIN SR, in women who have difficulties conceiving or who are undergoing
investigation of infertility.
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8.4 Pediatric Use
Safety and effectiveness in pediatric patients 14 years of age and younger has not been
established.
INDOCIN SR should not be prescribed for pediatric patients 14 years of age and younger
unless toxicity or lack of efficacy associated with other drugs warrants the risk.
In experience with more than 900 pediatric patients reported in the literature or to the
manufacturer who were treated with indomethacin immediate-release capsules, side effects in
pediatric patients were comparable to those reported in adults. Experience in pediatric
patients has been confined to the use of indomethacin immediate-release capsules.
If a decision is made to use indomethacin for pediatric patients two years of age or older,
such patients should be monitored closely and periodic assessment of liver function is
recommended. There have been cases of hepatotoxicity reported in pediatric patients with
juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a
suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage
should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are
available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day,
whichever is less. As symptoms subside, the total daily dosage should be reduced to the
lowest level required to control symptoms, or the drug should be discontinued.
8.5 Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated
serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated
benefit for the elderly patient outweighs these potential risks, start dosing at the low end of
the dosing range, and monitor patients for adverse effects [see Warnings and Precautions
(5.1, 5.2, 5.3, 5.6, 5.13)].
Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)];
physicians should remain alert to the possibility of such adverse effects in the elderly
Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and
the risk of adverse reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal function, use
caution in this patient population, and it may be useful to monitor renal function [see Clinical
Pharmacology (12.3)]
10 OVERDOSAGE
Symptoms following acute NSAID overdosages have been typically limited to lethargy,
drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with
supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure,
respiratory depression, and coma have occurred, but were rare [see Warnings and
Precautions (5.1, 5.2, 5.4, 5.6)].
Manage patients with symptomatic and supportive care following an NSAID overdosage.
There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams
in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in
symptomatic patients seen within four hours of ingestion or in patients with a large
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine,
hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1
800-222-1222).
11 DESCRIPTION
INDOCIN SR (indomethacin) extended-release capsules are nonsteroidal anti-inflammatory
drugs, available as capsules containing 75 mg of indomethacin, administered for oral use. The
chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The
molecular weight is 357.8. Its molecular formula is C19H16ClNO4 , and it has the following
chemical structure. structural formula
Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and
sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic
media and decomposes in strong alkali.
The inactive ingredients in INDOCIN SR Capsules, 75 mg include: cellulose, confectioner's
sugar, FD&C Blue 1, FD&C Blue 2, FD&C Red 3, gelatin, hydroxypropyl methylcellulose,
magnesium stearate, polyvinyl acetate- crotonic acid copolymer, starch, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Indomethacin has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of INDOCIN SR, like that of other NSAIDs, is not completely
understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin
concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize
afferent nerves and potentiate the action of bradykinin in inducing pain in animal models.
Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of
prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in
peripheral tissues.
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12.3 Pharmacokinetics
Absorption
Following single oral doses of indomethacin immediate-release capsules 25 mg or 50 mg,
indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and
2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin immediate-
release capsules are virtually 100% bioavailable, with 90% of the dose absorbed within
4 hours. A single 50 mg dose of INDOCIN oral suspension was found to be bioequivalent to
a 50 mg INDOCIN Capsule when each was administered with food. With a typical
therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations
of indomethacin are an average 1.4 times those following the first dose.
INDOCIN SR 75 mg are designed to release 25 mg of the drug initially and the remaining 50
mg over approximately 12 hours (90% of dose absorbed by 12 hours). When measured over a
24-hour period, the cumulative amount and time-course of indomethacin absorption from a
single indomethacin extended-release capsule are comparable to those of 3 doses of 25 mg
indomethacin immediate-release capsules given at 4-6 hour intervals
Plasma concentrations of indomethacin fluctuate less and are more sustained following
administration of indomethacin extended-release capsules than following administration of
25 mg indomethacin immediate-release capsules given at 4-6 hour intervals. In multiple-dose
comparisons, the mean daily steady-state plasma level of indomethacin attained with daily
administration of indomethacin extended-release capsules 75 mg was indistinguishable from
that following indomethacin immediate-release capsules 25 mg given at 0, 6 and 12 hours
daily. However, there was a significant difference in indomethacin plasma levels between the
two dosage regimens especially after 12 hours.
Distribution
Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of
therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain
barrier and the placenta, and appears in breast milk.
Elimination
Metabolism
Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and
desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation
of glucuronide conjugates of each metabolite and of indomethacin are formed.
Excretion
Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.
Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral
dose is recovered in urine as drug and metabolites (26% as indomethacin and its
glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life
of indomethacin is estimated to be about 4.5 hours.
Specific Populations
Pediatric: The pharmacokinetics of INDOCIN SR has not been investigated in pediatric
patients.
Race: Pharmacokinetic differences due to race have not been identified.
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Hepatic Impairment: The pharmacokinetics of INDOCIN SR has not been investigated in
patients with hepatic impairment.
Renal Impairment: The pharmacokinetics of INDOCIN SR has not been investigated in
patients with renal impairment [see Warnings and Precautions (5.6)].
Drug Interaction Studies
Aspirin:
In a study in normal volunteers, it was found that chronic concurrent administration of 3.6
g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug
Interactions (7)].
When NSAIDs were administered with aspirin, the protein binding of NSAIDs were
reduced, although the clearance of free NSAID was not altered. The clinical significance
of this interaction is not known. See Table 2 for clinically significant drug interactions of
NSAIDs with aspirin [see Drug Interactions (7)].
Diflunisal:
In normal volunteers receiving indomethacin, the administration of diflunisal decreased
the renal clearance and significantly increased the plasma levels of indomethacin [see
Drug Interactions (7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the
MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced
no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat
(dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to
1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis,
respectively).
Mutagenesis
Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in
vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and
the micronucleus test in mice.
Impairment of Fertility
Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two
generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter
reproduction study in rats (0.02 times the MRHD on a mg/m2 basis).
14 CLINICAL STUDIES
Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for
long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
INDOCIN SR affords relief of symptoms; it does not alter the progressive course of the
underlying disease.
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN SR suppresses inflammation in rheumatoid arthritis as demonstrated by relief of
pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with
indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling,
average number of joints involved, and morning stiffness; by increased mobility as
demonstrated by a decrease in walking time; and by improved functional capability as
demonstrated by an increase in grip strength. INDOCIN SR may enable the reduction of
steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis.
In such instances the steroid dosage should be reduced slowly and the patients followed very
closely for any possible adverse effects.
16 HOW SUPPLIED/STORAGE AND HANDLING
INDOCIN SR (indomethacin) extended-release capsules, 75 mg each, are opaque blue cap
and clear body, containing a mixture of blue and white pellets.
NDC 60951-774-60: unit of use bottles of 60
NDC 60951-774-70: bottles of 100
Storage
Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C
to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that
accompanies each prescription dispensed. Inform patients, families, or their caregivers of the
following information before initiating therapy with INDOCIN SR and periodically during
the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including
chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these
symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain,
dyspepsia, melena, and hematemesis to their health care provider. In the setting of
concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased
risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like”
symptoms). If these occur, instruct patients to stop INDOCIN SR and seek immediate
medical therapy [see Warnings and Precautions (5.3)].
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of
breath, unexplained weight gain, or edema and to contact their healthcare provider if such
symptoms occur [see Warnings and Precautions (5.5)].
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of
the face or throat). Instruct patients to seek immediate emergency help if these occur [see
Contraindications (4) and Warnings and Precautions (5.7)].
Serious Skin Reactions
Advise patients to stop INDOCIN SR immediately if they develop any type of rash and to
contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)].
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including
INDOCIN SR, may be associated with a reversible delay in ovulation [see Use in Specific
Populations (8.3)].
Fetal Toxicity
Inform pregnant women to avoid use of INDOCIN SR and other NSAIDs starting at 30
weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see
Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of INDOCIN SR with other NSAIDs or salicylates
(e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal
toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug
Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter”
medications for treatment of colds, fever, or insomnia.
Use of NSAIDs and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to
their healthcare provider [see Drug Interactions (7)].
Manufactured for and Distributed by:
Iroko Pharmaceuticals, LLC
Philadelphia, PA 19112
Issued: May/2016
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?
NSAIDs can cause serious side effects, including:
Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment
and may increase:
o with increasing doses of NSAIDs
o with longer use of NSAIDs
Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)."
Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may
have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.
Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the
mouth to the stomach), stomach and intestines:
o anytime during use
o without warning symptoms
o that may cause death
The risk of getting an ulcer or bleeding increases with:
o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
o increasing doses of NSAIDs
o longer use of NSAIDs
o smoking
o drinking alcohol
o older age
o poor health
o advanced liver disease
o bleeding problems
NSAIDs should only be used:
o exactly as prescribed
o at the lowest dose possible for your treatment
o for the shortest time needed
What are NSAIDs?
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions
such as different types of arthritis, menstrual cramps, and other types of short-term pain.
Who should not take NSAIDs?
Do not take NSAIDs:
if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
right before or after heart bypass surgery.
Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:
have liver or kidney problems
have high blood pressure
have asthma
are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking
NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.
are breastfeeding or plan to breast feed.
Tell your healthcare provider about all of the medicines you take, including prescription or over-the
counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with
each other and cause serious side effects. Do not start taking any new medicine without talking to your
healthcare provider first.
What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:
See “What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?”
new or worse high blood pressure
heart failure
liver problems including liver failure
kidney problems including kidney failure
low red blood cells (anemia)
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
life-threatening skin reactions
life-threatening allergic reactions
Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea,
vomiting, and dizziness.
Get emergency help right away if you get any of the following symptoms:
shortness of breath or trouble breathing
chest pain
weakness in one part or side of your body
slurred speech
swelling of the face or throat
Stop taking your NSAID and call your healthcare provider right away if you get any of the following
symptoms:
nausea
more tired or weaker than usual
diarrhea
itching
your skin or eyes look yellow
indigestion or stomach pain
flu-like symptoms
vomit blood
there is blood in your bowel movement or
it is black and sticky like tar
unusual weight gain
skin rash or blisters with fever
swelling of the arms, legs, hands and
feet
If you take too much of your NSAID, call your healthcare provider or get medical help right away.
These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or
pharmacist about NSAIDs.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Other information about NSAIDs
Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in
the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare
provider before using over-the-counter NSAIDs for more than 10 days.
General information about the safe and effective use of NSAIDs
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the
same symptoms that you have. It may harm them.
If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist
or healthcare provider for information about NSAIDs that is written for health professionals.
Manufactured for and Distributed by:
Iroko Pharmaceuticals, LLC
One Kew Place
150 Rouse Boulevard
Philadelphia, PA 19112
For more information, go to www.iroko.com or call 1-877-757-0676
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued or Revised: May 2016
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
INDOCIN® SR safely and effectively. See full prescribing information for
INDOCIN SR.
INDOCIN SR (indomethacin) extended-release capsules for oral use
Initial U.S. Approval: 1965
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
See full prescribing information for complete boxed warning.
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased
risk of serious cardiovascular thrombotic events, including myocardial
infarction and stroke, which can be fatal. This risk may occur early in
treatment and may increase with duration of use (5.1)
INDOCIN SR is contraindicated in the setting of coronary artery
bypass graft (CABG) surgery (4, 5.1)
NSAIDs cause an increased risk of serious gastrointestinal (GI)
adverse events including bleeding, ulceration, and perforation of the
stomach or intestines, which can be fatal. These events can occur at
any time during use and without warning symptoms. Elderly patients
and patients with a prior history of peptic ulcer disease and/or GI
bleeding are at greater risk for serious GI events (5.2)
RECENT MAJOR CHANGES
Boxed Warning
5/2016
Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016
Warnings and Precautions, Heart Failure and Edema (5.5)
5/2016
INDICATIONS AND USAGE
INDOCIN SR is a nonsteroidal anti-inflammatory drug indicated for:
Moderate to severe rheumatoid arthritis including acute flares of chronic
disease
Moderate to severe ankylosing spondylitis
Moderate to severe osteoarthritis
Acute painful shoulder (bursitis and/or tendinitis) (1)
DOSAGE AND ADMINISTRATION
Use the lowest effective dosage for shortest duration consistent with
individual patient treatment goals (2.1)
The dosage for moderate to severe rheumatoid arthritis including acute
flares of chronic disease; moderate to severe ankylosing spondylitis; and
moderate to severe osteoarthritis is one INDOCIN SR 75 mg capsule daily
(2.2)
The dosage for acute painful shoulder (bursitis and/or tendinitis) is one
INDOCIN SR 75 mg capsule once or twice daily (2.3)
DOSAGE FORMS AND STRENGTHS
INDOCIN SR (indomethacin) extended-releasde capsules: 75 mg (3)
CONTRAINDICATIONS
Known hypersensitivity to indomethacin or any components of the drug
product (4)
History of asthma, urticaria, or other allergic-type reactions after taking
aspirin or other NSAIDs (4)
In the setting of CABG surgery (4)
WARNINGS AND PRECAUTIONS
Hepatotoxicity: Inform patients of warning signs and symptoms of
hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if
clinical signs and symptoms of liver disease develop (5.3)
Hypertension: Patients taking some antihypertensive medications may have
impaired response to these therapies when taking NSAIDs. Monitor blood
pressure (5.4, 7)
Heart Failure and Edema: Avoid use of INDOCIN SR in patients with
severe heart failure unless benefits are expected to outweigh risk of
worsening heart failure (5.5)
Renal Toxicity: Monitor renal function in patients with renal or hepatic
impairment, heart failure, dehydration, or hypovolemia. Avoid use of
INDOCIN SR in patients with advanced renal disease unless benefits are
expected to outweigh risk of worsening renal function (5.6)
Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction
occurs (5.7)
Exacerbation of Asthma Related to Aspirin Sensitivity: INDOCIN SR is
contraindicated in patients with aspirin-sensitive asthma. Monitor patients
with preexisting asthma (without aspirin sensitivity) (5.8)
Serious Skin Reactions: Discontinue INDOCIN SR at first appearance of
skin rash or other signs of hypersensitivity (5.9)
Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant
women starting at 30 weeks gestation (5.10, 8.1)
Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with
any signs or symptoms of anemia (5.11, 7)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥ 3%) are headache, dizziness,
dyspepsia and nausea. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Iroko
Pharmaceuticals, LLC at 1-877-757-0676 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
DRUG INTERACTIONS
Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs):
Monitor patients for bleeding who are concomitantly taking INDOCIN SR
with drugs that interfere with hemostasis. Concomitant use of INDOCIN
SR and analgesic doses of aspirin is not generally recommended (7)
ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers:
Concomitant use with INDOCIN SR may diminish the antihypertensive
effect of these drugs. Monitor blood pressure (7)
ACE Inhibitors and ARBs: Concomitant use with INDOCIN SR in elderly,
volume depleted, or those with renal impairment may result in deterioration
of renal function. In such high risk patients, monitor for signs of worsening
renal function (7)
Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide
diuretics. Monitor patients to assure diuretic efficacy including
antihypertensive effects (7)
Digoxin: Concomitant use with INDOCIN SR can increase serum
concentration and prolong half-life of digoxin. Monitor serum digoxin
levels (7)
USE IN SPECIFIC POPULATIONS
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases
the risk of premature closure of the fetal ductus arteriosus. Avoid use of
NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1)
Infertility: NSAIDs are associated with reversible infertility. Consider
withdrawal of INDOCIN SR in women who have difficulties conceiving (8.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised 5/2016
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Instructions
2.2
Moderate to severe rheumatoid arthritis including acute
flares of chronic disease; moderate to severe ankylosing
spondylitis; and moderate to severe osteoarthritis
2.3
Acute painful shoulder (bursitis and/or tendinitis)
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Cardiovascular Thrombotic Events
5.2
Gastrointestinal Bleeding, Ulceration, and Perforation
5.3
Hepatotoxicity
5.4
Hypertension
5.5
Heart Failure and Edema
5.6
Renal Toxicity and Hyperkalemia
5.7
Anaphylactic Reactions
5.8
Exacerbation of Asthma Related to Aspirin Sensitivity
5.9
Serious Skin Reactions
5.10
Premature Closure of Fetal Ductus Arteriosus
5.11
Hematologic Toxicity
5.12
Masking of Inflammation and Fever
5.13
Laboratory Monitoring
5.14
Central Nervous System Effects
5.15
Ocular Effects
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
Cardiovascular Thrombotic Events
• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious
cardiovascular thrombotic events, including myocardial infarction and stroke,
which can be fatal. This risk may occur early in treatment and may increase with
duration of use [see Warnings and Precautions (5.1)].
• INDOCIN SR is contraindicated in the setting of coronary artery bypass graft
(CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events
including bleeding, ulceration, and perforation of the stomach or intestines, which
can be fatal. These events can occur at any time during use and without warning
symptoms. Elderly patients and patients with a prior history of peptic ulcer disease
and/or GI bleeding are at greater risk for serious GI events [see Warnings and
Precautions (5.2)].
1
INDICATIONS AND USAGE
INDOCIN SR is indicated for:
Moderate to severe rheumatoid arthritis including acute flares of chronic disease
Moderate to severe ankylosing spondylitis
Moderate to severe osteoarthritis
Acute painful shoulder (bursitis and/or tendinitis)
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Instructions
Carefully consider the potential benefits and risks of INDOCIN SR and other treatment
options before deciding to use INDOCIN SR. Use the lowest effective dosage for the shortest
duration consistent with individual patient treatment goals [see Warnings and Precautions
(5)].
After observing the response to initial therapy with indomethacin, the dose and frequency
should be adjusted to suit an individual patient’s needs.
Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore,
every effort should be made to determine the lowest effective dosage for the individual
patient.
THIS SECTION PREDOMINANTLY REFERENCES THE INDOMETHACIN
IMMEDIATE-RELEASE CAPSULE ORAL DOSAGE AND IS INTENDED TO PROVIDE
GUIDANCE IN USING INDOCIN SR EXTENDED-RELEASE CAPSULES, 75 MG
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN SR, 75 mg once a day can be substituted for indomethacin immediate-release
capsules, 25 mg three times a day. However, there will be significant differences
between the two dosage regimens in indomethacin blood levels, especially after 12 hours
[see Clinical Pharmacology (12)]. In addition, INDOCIN SR, 75 mg twice a day can be
substituted for indomethacin immediate-release capsules, USP 50 mg three times a day.
INDOCIN SR may be substituted for all the indications for indomethacin immediate-
release capsules, USP except acute gouty arthritis.
Dosage Recommendations for Active Stages of the Following:
2.2 Moderate to severe rheumatoid arthritis including acute flares of
chronic disease; moderate to severe ankylosing spondylitis; and
moderate to severe osteoarthritis
Indomethacin immediate-release capsules, 25 mg twice a day or three times a day. If this is
well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing
symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily
dose of 150 - 200 mg is reached. Doses above this amount generally do not increase the
effectiveness of the drug.
In patients who have persistent night pain and/or morning stiffness, the giving of a large
portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in
affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic
rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by
50 mg daily.
If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a
tolerated dose and observe the patient closely.
If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under
control, an attempt to reduce the daily dose should be made repeatedly until the patient is
receiving the smallest effective dose or the drug is discontinued.
Careful instructions to, and observations of, the individual patient are essential to the
prevention of serious, irreversible, including fatal, adverse reactions.
As advancing years appear to increase the possibility of adverse reactions, INDOCIN SR
should be used with greater care in the elderly [see Use in Specific Populations (8.5)].
2.3 Acute painful shoulder (bursitis and/or tendinitis)
Indomethacin immediate-release capsules 75-150 mg daily in 3 or 4 divided doses.
Discontinue INDOCIN SR treatment after the signs and symptoms of inflammation have
been controlled for several days. The usual course of therapy is 7-14 days.
3 DOSAGE FORMS AND STRENGTHS
INDOCIN SR (indomethacin) extended-release capsules 75 mg - opaque blue cap and clear
body hard shell gelatin capsules, containing a mixture of blue and white pellets, printed with
both 157 and WPPh.
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4
CONTRAINDICATIONS
INDOCIN SR is contraindicated in the following patients:
Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to
indomethacin or any components of the drug product [see Warnings and Precautions
(5.7, 5.9)]
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other
NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported
in such patients [see Warnings and Precautions (5.7, 5.8)]
In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and
Precautions (5.1)]
5
WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years
duration have shown an increased risk of serious cardiovascular (CV) thrombotic events,
including myocardial infarction (MI) and stroke, which can be fatal. Based on available data,
it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative
increase in serious CV thrombotic events over baseline conferred by NSAID use appears to
be similar in those with and without known CV disease or risk factors for CV disease.
However, patients with known CV disease or risk factors had a higher absolute incidence of
excess serious CV thrombotic events, due to their increased baseline rate. Some observational
studies found that this increased risk of serious CV thrombotic events began as early as the
first weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the
lowest effective dose for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, throughout the entire treatment course, even in the
absence of previous CV symptoms. Patients should be informed about the symptoms of
serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of
serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and
an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events
[see Warnings and Precautions (5.2)].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in
the first 10–14 days following CABG surgery found an increased incidence of myocardial
infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see
Contraindications (4)].
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Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that
patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction,
CV-related death, and all-cause mortality beginning in the first week of treatment. In this
same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in
NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed
patients. Although the absolute rate of death declined somewhat after the first year post-MI,
the increased relative risk of death in NSAID users persisted over at least the next four years
of follow-up.
Avoid the use of INDOCIN SR in patients with a recent MI unless the benefits are expected
to outweigh the risk of recurrent CV thrombotic events. If INDOCIN SR is used in patients
with a recent MI, monitor patients for signs of cardiac ischemia.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach,
small intestine, or large intestine, which can be fatal. These serious adverse events can occur
at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one
in five patients who develop a serious upper GI adverse event on NSAID therapy is
symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in
approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated
for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had
a greater than 10-fold increased risk for developing a GI bleed compared to patients without
these risk factors. Other factors that increase the risk of GI bleeding in patients treated with
NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids,
aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of
alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI
events occurred in elderly or debilitated patients. Additionally, patients with advanced liver
disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the
increased risk of bleeding. For such patients, as well as those with active GI bleeding,
consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID
therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment,
and discontinue INDOCIN SR until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor
patients more closely for evidence of GI bleeding [see Drug Interactions (7)].
Reference ID: 3928095
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5.3 Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been
reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare,
sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis,
and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients
treated with NSAIDs including indomethacin.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like"
symptoms). If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue INDOCIN SR
immediately, and perform a clinical evaluation of the patient.
5.4 Hypertension
NSAIDs, including INDOCIN SR, can lead to new onset of hypertension or worsening of
preexisting hypertension, either of which may contribute to the increased incidence of CV
events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or
loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug
Interactions (7)].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the
course of therapy.
5.5 Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized
controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart
failure in COX-2 selective-treated patients and nonselective NSAID-treated patients
compared to placebo-treated patients. In a Danish National Registry study of patients with
heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with
NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to
treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor
blockers [ARBs]) [see Drug Interactions (7)].
Avoid the use of INDOCIN SR in patients with severe heart failure unless the benefits are
expected to outweigh the risk of worsening heart failure. If INDOCIN SR is used in patients
with severe heart failure, monitor patients for signs of worsening heart failure.
5.6 Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal
injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In these patients, administration of
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an NSAID may cause a dose-dependent reduction in prostaglandin formation and,
secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients
at greatest risk of this reaction are those with impaired renal function, dehydration,
hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or
ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to
the pretreatment state.
No information is available from controlled clinical studies regarding the use of INDOCIN
SR in patients with advanced renal disease. The renal effects of INDOCIN SR may hasten the
progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN
SR. Monitor renal function in patients with renal or hepatic impairment, heart failure,
dehydration, or hypovolemia during use of INDOCIN SR [see Drug Interactions (7)]. Avoid
the use of INDOCIN SR in patients with advanced renal disease unless the benefits are
expected to outweigh the risk of worsening renal function. If INDOCIN SR is used in patients
with advanced renal disease, monitor patients for signs of worsening renal function.
It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a
maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four
healthy volunteers. Indomethacin and triamterene should not be administered together.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with
use of NSAIDs, even in some patients without renal impairment. In patients with normal
renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism
state.
Both Indomethacin and potassium-sparing diuretics may be associated with increased serum
potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on
potassium levels and renal function should be considered when these agents are administered
concurrently.
5.7 Anaphylactic Reactions
Indomethacin has been associated with anaphylactic reactions in patients with and without
known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see
Contraindications (4) and Warnings and Precautions (5.8)].
Seek emergency help if an anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may
include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal
bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity
between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients,
INDOCIN SR is contraindicated in patients with this form of aspirin sensitivity [see
Contraindications (4)]. When INDOCIN SR is used in patients with preexisting asthma
(without known aspirin sensitivity), monitor patients for changes in the signs and symptoms
of asthma.
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5.9 Serious Skin Reactions
NSAIDs, including indomethacin, can cause serious skin adverse reactions such as
exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis
(TEN), which can be fatal. These serious events may occur without warning. Inform patients
about the signs and symptoms of serious skin reactions, and to discontinue the use of
INDOCIN SR at the first appearance of skin rash or any other sign of hypersensitivity.
INDOCIN SR is contraindicated in patients with previous serious skin reactions to NSAIDs
[see Contraindications (4)].
5.10 Premature Closure of Fetal Ductus Arteriosus
Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of
NSAIDs, including INDOCIN SR, in pregnant women starting at 30 weeks of gestation (third
trimester) [see Use in Specific Populations (8.1)].
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood
loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated
with INDOCIN SR has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including INDOCIN SR, may increase the risk of bleeding events. Co-morbid
conditions, such as coagulation disorders, or concomitant use of warfarin, other
anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and
serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these
patients for signs of bleeding [see Drug Interactions (7)].
5.12 Masking of Inflammation and Fever
The pharmacological activity of INDOCIN SR in reducing inflammation, and possibly fever,
may diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning
symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC
and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].
5.14 Central Nervous System Effects
INDOCIN SR may aggravate depression or other psychiatric disturbances, epilepsy, and
parkinsonism, and should be used with considerable caution in patients with these conditions.
Discontinue INDOCIN SR if severe CNS adverse reactions develop.
INDOCIN SR may cause drowsiness; therefore, caution patients about engaging in activities
requiring mental alertness and motor coordination, such as driving a car. Indomethacin may
also cause headache. Headache which persists despite dosage reduction requires cessation of
therapy with INDOCIN SR.
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5.15 Ocular Effects
Corneal deposits and retinal disturbances, including those of the macula, have been observed
in some patients who had received prolonged therapy with INDOCIN SR. Be alert to the
possible association between the changes noted and INDOCIN SR. It is advisable to
discontinue therapy if such changes are observed. Blurred vision may be a significant
symptom and warrants a thorough ophthalmological examination. Since these changes may
be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients
receiving prolonged therapy. INDOCIN SR is not indicated for long-term treatment.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling:
Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
Hepatotoxicity [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Heart Failure and Edema [see Warnings and Precautions (5.5)]
Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
Anaphylactic Reactions [see Warnings and Precautions (5.7)]
Serious Skin Reactions [see Warnings and Precautions (5.9)]
Hematologic Toxicity [see Warnings and Precautions (5.11)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in clinical practice.
In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities
was significantly higher in the group receiving indomethacin immediate-release capsules
than in the group taking indomethacin suppositories or placebo.
In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis,
however, the incidence of upper gastrointestinal adverse effects with indomethacin
immediate-release capsules or suppositories was comparable. The incidence of lower
gastrointestinal adverse effects was greater in the suppository group.
The adverse reactions for indomethacin immediate-release capsules listed in the following
table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence
less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled
clinical trials reported in the literature (1,092 patients). The incidence for group (2) was
based on reports in clinical trials, in the literature, and on voluntary reports since marketing.
The probability of a causal relationship exists between INDOCIN and these adverse
reactions, some of which have been reported only rarely.
The adverse reactions reported with indomethacin immediate-release capsules may occur
with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in
patients who have received the capsules.
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Table 1
Summary of Adverse Reactions for INDOCIN Capsules
Incidence greater than 1%
Incidence less than 1%
GASTROINTESTINAL
nausea * with or
without vomiting
dyspepsia * (including
indigestion, heartburn and
epigastric pain)
diarrhea
abdominal distress or pain
constipation
anorexia
bloating (includes distension)
flatulence
peptic ulcer
gastroenteritis
rectal bleeding
proctitis
single or multiple ulcerations,
including perforation and hemorrhage
of the esophagus, stomach,
duodenum or small and large
intestines
intestinal ulceration associated with
stenosis and obstruction
gastrointestinal bleeding without
obvious ulcer formation and
perforation of preexisting
sigmoid lesions (diverticulum,
carcinoma, etc.) development
of ulcerative colitis and
regional ileitis
ulcerative stomatitis
toxic hepatitis and jaundice
(some fatal cases have been
reported)
intestinal strictures
(diaphragms)
CENTRAL NERVOUS SYSTEM
headache (11.7%)
dizziness *
vertigo
somnolence
depression and fatigue
(including malaise and
listlessness)
anxiety (includes nervousness)
muscle weakness
involuntary muscle movements
insomnia
muzziness
psychic disturbances including
psychotic episodes
mental confusion
drowsiness
light-headedness
syncope
paresthesia
aggravation of epilepsy and
parkinsonism
depersonalization
coma
peripheral neuropathy
convulsion
dysarthria
SPECIAL SENSES
tinnitus
ocular — corneal deposits and retinal
disturbances, including those of
the macula, have been reported in
some patients on prolonged therapy with
INDOCIN
blurred vision
diplopia
hearing disturbances, deafness
CARDIOVASCULAR
None
hypertension
hypotension
tachycardia
chest pain
congestive heart failure
arrhythmia; palpitations
METABOLIC
None
edema
weight gain
fluid retention
flushing or sweating
hyperglycemia
glycosuria
hyperkalemia
INTEGUMENTARY
none
pruritus
rash; urticaria
petechiae or ecchymosis
exfoliative dermatitis
erythema nodosum
loss of hair
Stevens-Johnson syndrome
erythema multiforme
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Incidence greater than 1%
Incidence less than 1%
toxic epidermal necrolysis
HEMATOLOGIC
None
leukopenia
bone marrow depression
anemia secondary to obvious or occult
gastrointestinal bleeding
aplastic anemia
hemolytic anemia
agranulocytosis
thrombocytopenic purpura
disseminated intravascular
coagulation
HYPERSENSITIVITY
None
acute anaphylaxis
acute respiratory distress
rapid fall in blood pressure resembling
a shock-like state
angioedema
dyspnea
asthma
purpura
angiitis
pulmonary edema
fever
GENITOURINARY
None
hematuria
vaginal bleeding
proteinuria
nephrotic syndrome
interstitial nephritis
BUN elevation
renal insufficiency, including renal
failure
MISCELLANEOUS
None
epistaxis
breast changes, including enlargement
and tenderness, or gynecomastia
* Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than 3% of the
patients are unmarked.)
Causal relationship unknown: Other reactions have been reported but occurred under
circumstances where a causal relationship could not be established. However, in these rarely
reported events, the possibility cannot be excluded. Therefore, these observations are being
listed to serve as alerting information to physicians:
Cardiovascular: Thrombophlebitis
Hematologic: Although there have been several reports of leukemia, the supporting
information is weak
Genitourinary: Urinary frequency
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with
Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal
anti-inflammatory agents, including indomethacin, sometimes with fatal outcome.
7
DRUG INTERACTIONS
See Table 2 for clinically significant drug interactions with indomethacin.
Table 2
Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact:
Indomethacin and anticoagulants such as warfarin have a synergistic effect on
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bleeding. The concomitant use of indomethacin and anticoagulants have an increased
risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and
cohort epidemiological studies showed that concomitant use of drugs that interfere
with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than
an NSAID alone.
Intervention:
Monitor patients with concomitant use of INDOCIN SR with anticoagulants (e.g.,
warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors
(SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding
[see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic
doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs
alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated
with a significantly increased incidence of GI adverse reactions as compared to use of
the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:
Concomitant use of INDOCIN SR and analgesic doses of aspirin is not generally
recommended because of the increased risk of bleeding [see Warnings and Precautions
(5.11)].
INDOCIN SR is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme
(ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including
propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or
have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs
may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Intervention:
During concomitant use of INDOCIN SR and ACE-inhibitors, ARBs, or beta-
blockers, monitor blood pressure to ensure that the desired blood pressure is
obtained.
During concomitant use of INDOCIN SR and ACE-inhibitors or ARBs in patients
who are elderly, volume-depleted, or have impaired renal function, monitor for signs
of worsening renal function [see Warnings and Precautions (5.6)].
When these drugs are administered concomitantly, patients should be adequately
hydrated. Assess renal function at the beginning of the concomitant treatment and
periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced
the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some
patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin
synthesis.
It has been reported that the addition of triamterene to a maintenance schedule of
INDOCIN SR resulted in reversible acute renal failure in two of four healthy
volunteers. INDOCIN SR and triamterene should not be administered together.
Both INDOCIN SR and potassium-sparing diuretics may be associated with increased
serum potassium levels. The potential effects of INDOCIN SR and potassium-sparing
diuretics on potassium levels and renal function should be considered when these agents
are administered concurrently.
Intervention:
Indomethacin and triamterene should not be administered together.
During concomitant use of INDOCIN SR with diuretics, observe patients for signs of
worsening renal function, in addition to assuring diuretic efficacy including
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antihypertensive effects.
Be aware that indomethacin and potassium-sparing diuretics may both be associated
with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:
The concomitant use of indomethacin with digoxin has been reported to increase the
serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of INDOCIN SR and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal
lithium clearance. The mean minimum lithium concentration increased 15%, and the
renal clearance decreased by approximately 20%. This effect has been attributed to
NSAID inhibition of renal prostaglandin synthesis.
Intervention:
During concomitant use of INDOCIN SR and lithium, monitor patients for signs of
lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate
toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of INDOCIN SR and methotrexate, monitor patients for
methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of INDOCIN SR and cyclosporine may increase cyclosporine’s
nephrotoxicity.
Intervention:
During concomitant use of INDOCIN SR and cyclosporine, monitor patients for signs
of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal,
salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see
Warnings and Precautions (5.2)].
Combined use with diflunisal may be particularly hazardous because diflunisal causes
significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)].
In some patients, combined use of indomethacin and diflunisal has been associated with
fatal gastrointestinal hemorrhage.
Intervention:
The concomitant use of indomethacin with other NSAIDs or salicylates, especially
diflunisal, is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of INDOCIN SR and pemetrexed may increase the risk of
pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed
prescribing information).
Intervention:
During concomitant use of INDOCIN SR and pemetrexed, in patients with renal
impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for
myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be
avoided for a period of two days before, the day of, and two days following
administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs
with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs
should interrupt dosing for at least five days before, the day of, and two days following
pemetrexed administration.
Probenecid
Clinical Impact:
When indomethacin is given to patients receiving probenecid, the plasma levels of
indomethacin are likely to be increased.
Reference ID: 3928095
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Intervention:
During the concomitant use of INDOCIN SR and probenecid, a lower total daily dosage
of indomethacin may produce a satisfactory therapeutic effect. When increases in the
dose of indomethacin are made, they should be made carefully and in small increments.
Effects on Laboratory Tests
Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced
by furosemide administration, or salt or volume depletion. These facts should be considered when
evaluating plasma renin activity in hypertensive patients.
False-negative results in the dexamethasone suppression test (DST) in patients being treated
with indomethacin have been reported. Thus, results of the DST should be interpreted with
caution in these patients.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Use of NSAIDs, including INDOCIN SR, during the third trimester of pregnancy increases
the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including
INDOCIN SR, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of INDOCIN SR in pregnant women.
Data from observational studies regarding potential embryofetal risks of NSAID use in
women in the first or second trimesters of pregnancy are inconclusive. In the general U.S.
population, all clinically recognized pregnancies, regardless of drug exposure, have a
background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal
reproduction studies retarded fetal ossification was observed with administration of
indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively,
the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant
mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and
fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the
last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1
and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins
have been shown to have an important role in endometrial vascular permeability, blastocyst
implantation, and decidualization. In animal studies, administration of prostaglandin
synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation
loss.
Clinical Considerations
Labor or Delivery
There are no studies on the effects of INDOCIN SR during labor or delivery. In animal
studies, NSAIDs, including indomethacin, inhibit prostaglandin synthesis, cause delayed
parturition, and increase the incidence of stillbirth.
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Data
Animal data
Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and
4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and
0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the
decreased average fetal weights, no increase in fetal malformations was observed as
compared with control groups. Other studies in mice reported in the literature using higher
doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal
toxicity and death, increased fetal resorptions, and fetal malformations.
In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1
times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an
increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however
no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control
groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0
mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal
necrosis at either dose level.
8.2 Lactation
Risk Summary
Based on available published clinical data, indomethacin may be present in human milk. The
developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for INDOCIN SR and any potential adverse effects on the breastfed
infant from the INDOCIN SR or from the underlying maternal condition.
Data
In one study, levels of indomethacin in breast milk were below the sensitivity of the assay
(<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally
daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average
concentration present in breast milk was estimated to be 0.27% of the maternal weight-
adjusted dose. In another study indomethacin levels were measured in breast milk of eight
postpartum women using doses of 75 mg daily and the results were used to calculate an
estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was
less than 30 mcg/day or 4.5 mcg/ kg/day assuming breast milk intake of 150 mL/kg/day.
This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for
treatment of patent ductus arteriosus.
8.3 Females and Males of Reproductive Potential
Infertility
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including
INDOCIN SR, may delay or prevent rupture of ovarian follicles, which has been associated
with reversible infertility in some women. Published animal studies have shown that
administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-
mediated follicular rupture required for ovulation. Small studies in women treated with
NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs,
including INDOCIN SR, in women who have difficulties conceiving or who are undergoing
investigation of infertility.
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.4 Pediatric Use
Safety and effectiveness in pediatric patients 14 years of age and younger has not been
established.
INDOCIN SR should not be prescribed for pediatric patients 14 years of age and younger
unless toxicity or lack of efficacy associated with other drugs warrants the risk.
In experience with more than 900 pediatric patients reported in the literature or to the
manufacturer who were treated with indomethacin immediate-release capsules, side effects in
pediatric patients were comparable to those reported in adults. Experience in pediatric
patients has been confined to the use of indomethacin immediate-release capsules.
If a decision is made to use indomethacin for pediatric patients two years of age or older,
such patients should be monitored closely and periodic assessment of liver function is
recommended. There have been cases of hepatotoxicity reported in pediatric patients with
juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a
suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage
should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are
available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day,
whichever is less. As symptoms subside, the total daily dosage should be reduced to the
lowest level required to control symptoms, or the drug should be discontinued.
8.5 Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated
serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated
benefit for the elderly patient outweighs these potential risks, start dosing at the low end of
the dosing range, and monitor patients for adverse effects [see Warnings and Precautions
(5.1, 5.2, 5.3, 5.6, 5.13)].
Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)];
physicians should remain alert to the possibility of such adverse effects in the elderly
Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and
the risk of adverse reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal function, use
caution in this patient population, and it may be useful to monitor renal function [see Clinical
Pharmacology (12.3)]
10 OVERDOSAGE
Symptoms following acute NSAID overdosages have been typically limited to lethargy,
drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with
supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure,
respiratory depression, and coma have occurred, but were rare [see Warnings and
Precautions (5.1, 5.2, 5.4, 5.6)].
Manage patients with symptomatic and supportive care following an NSAID overdosage.
There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams
in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in
symptomatic patients seen within four hours of ingestion or in patients with a large
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine,
hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1
800-222-1222).
11 DESCRIPTION
INDOCIN SR (indomethacin) extended-release capsules are nonsteroidal anti-inflammatory
drugs, available as capsules containing 75 mg of indomethacin, administered for oral use. The
chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The
molecular weight is 357.8. Its molecular formula is C19H16ClNO4 , and it has the following
chemical structure. structural formula
Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and
sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic
media and decomposes in strong alkali.
The inactive ingredients in INDOCIN SR Capsules, 75 mg include: cellulose, confectioner's
sugar, FD&C Blue 1, FD&C Blue 2, FD&C Red 3, gelatin, hydroxypropyl methylcellulose,
magnesium stearate, polyvinyl acetate- crotonic acid copolymer, starch, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Indomethacin has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of INDOCIN SR, like that of other NSAIDs, is not completely
understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin
concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize
afferent nerves and potentiate the action of bradykinin in inducing pain in animal models.
Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of
prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in
peripheral tissues.
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12.3 Pharmacokinetics
Absorption
Following single oral doses of indomethacin immediate-release capsules 25 mg or 50 mg,
indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and
2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin immediate-
release capsules are virtually 100% bioavailable, with 90% of the dose absorbed within
4 hours. A single 50 mg dose of INDOCIN oral suspension was found to be bioequivalent to
a 50 mg INDOCIN Capsule when each was administered with food. With a typical
therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations
of indomethacin are an average 1.4 times those following the first dose.
INDOCIN SR 75 mg are designed to release 25 mg of the drug initially and the remaining 50
mg over approximately 12 hours (90% of dose absorbed by 12 hours). When measured over a
24-hour period, the cumulative amount and time-course of indomethacin absorption from a
single indomethacin extended-release capsule are comparable to those of 3 doses of 25 mg
indomethacin immediate-release capsules given at 4-6 hour intervals
Plasma concentrations of indomethacin fluctuate less and are more sustained following
administration of indomethacin extended-release capsules than following administration of
25 mg indomethacin immediate-release capsules given at 4-6 hour intervals. In multiple-dose
comparisons, the mean daily steady-state plasma level of indomethacin attained with daily
administration of indomethacin extended-release capsules 75 mg was indistinguishable from
that following indomethacin immediate-release capsules 25 mg given at 0, 6 and 12 hours
daily. However, there was a significant difference in indomethacin plasma levels between the
two dosage regimens especially after 12 hours.
Distribution
Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of
therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain
barrier and the placenta, and appears in breast milk.
Elimination
Metabolism
Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and
desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation
of glucuronide conjugates of each metabolite and of indomethacin are formed.
Excretion
Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.
Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral
dose is recovered in urine as drug and metabolites (26% as indomethacin and its
glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life
of indomethacin is estimated to be about 4.5 hours.
Specific Populations
Pediatric: The pharmacokinetics of INDOCIN SR has not been investigated in pediatric
patients.
Race: Pharmacokinetic differences due to race have not been identified.
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hepatic Impairment: The pharmacokinetics of INDOCIN SR has not been investigated in
patients with hepatic impairment.
Renal Impairment: The pharmacokinetics of INDOCIN SR has not been investigated in
patients with renal impairment [see Warnings and Precautions (5.6)].
Drug Interaction Studies
Aspirin:
In a study in normal volunteers, it was found that chronic concurrent administration of 3.6
g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug
Interactions (7)].
When NSAIDs were administered with aspirin, the protein binding of NSAIDs were
reduced, although the clearance of free NSAID was not altered. The clinical significance
of this interaction is not known. See Table 2 for clinically significant drug interactions of
NSAIDs with aspirin [see Drug Interactions (7)].
Diflunisal:
In normal volunteers receiving indomethacin, the administration of diflunisal decreased
the renal clearance and significantly increased the plasma levels of indomethacin [see
Drug Interactions (7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the
MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced
no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat
(dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to
1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis,
respectively).
Mutagenesis
Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in
vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and
the micronucleus test in mice.
Impairment of Fertility
Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two
generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter
reproduction study in rats (0.02 times the MRHD on a mg/m2 basis).
14 CLINICAL STUDIES
Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for
long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
INDOCIN SR affords relief of symptoms; it does not alter the progressive course of the
underlying disease.
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN SR suppresses inflammation in rheumatoid arthritis as demonstrated by relief of
pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with
indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling,
average number of joints involved, and morning stiffness; by increased mobility as
demonstrated by a decrease in walking time; and by improved functional capability as
demonstrated by an increase in grip strength. INDOCIN SR may enable the reduction of
steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis.
In such instances the steroid dosage should be reduced slowly and the patients followed very
closely for any possible adverse effects.
16 HOW SUPPLIED/STORAGE AND HANDLING
INDOCIN SR (indomethacin) extended-release capsules, 75 mg each, are opaque blue cap
and clear body, containing a mixture of blue and white pellets.
NDC 60951-774-60: unit of use bottles of 60
NDC 60951-774-70: bottles of 100
Storage
Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C
to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that
accompanies each prescription dispensed. Inform patients, families, or their caregivers of the
following information before initiating therapy with INDOCIN SR and periodically during
the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including
chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these
symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain,
dyspepsia, melena, and hematemesis to their health care provider. In the setting of
concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased
risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like”
symptoms). If these occur, instruct patients to stop INDOCIN SR and seek immediate
medical therapy [see Warnings and Precautions (5.3)].
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of
breath, unexplained weight gain, or edema and to contact their healthcare provider if such
symptoms occur [see Warnings and Precautions (5.5)].
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of
the face or throat). Instruct patients to seek immediate emergency help if these occur [see
Contraindications (4) and Warnings and Precautions (5.7)].
Serious Skin Reactions
Advise patients to stop INDOCIN SR immediately if they develop any type of rash and to
contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)].
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including
INDOCIN SR, may be associated with a reversible delay in ovulation [see Use in Specific
Populations (8.3)].
Fetal Toxicity
Inform pregnant women to avoid use of INDOCIN SR and other NSAIDs starting at 30
weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see
Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of INDOCIN SR with other NSAIDs or salicylates
(e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal
toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug
Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter”
medications for treatment of colds, fever, or insomnia.
Use of NSAIDs and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to
their healthcare provider [see Drug Interactions (7)].
Manufactured for and Distributed by:
Iroko Pharmaceuticals, LLC
Philadelphia, PA 19112
Issued: May/2016
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?
NSAIDs can cause serious side effects, including:
Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment
and may increase:
o with increasing doses of NSAIDs
o with longer use of NSAIDs
Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)."
Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may
have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.
Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the
mouth to the stomach), stomach and intestines:
o anytime during use
o without warning symptoms
o that may cause death
The risk of getting an ulcer or bleeding increases with:
o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
o increasing doses of NSAIDs
o longer use of NSAIDs
o smoking
o drinking alcohol
o older age
o poor health
o advanced liver disease
o bleeding problems
NSAIDs should only be used:
o exactly as prescribed
o at the lowest dose possible for your treatment
o for the shortest time needed
What are NSAIDs?
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions
such as different types of arthritis, menstrual cramps, and other types of short-term pain.
Who should not take NSAIDs?
Do not take NSAIDs:
if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
right before or after heart bypass surgery.
Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:
have liver or kidney problems
have high blood pressure
have asthma
are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking
NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.
are breastfeeding or plan to breast feed.
Tell your healthcare provider about all of the medicines you take, including prescription or over-the
counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with
each other and cause serious side effects. Do not start taking any new medicine without talking to your
healthcare provider first.
What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:
See “What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?”
new or worse high blood pressure
heart failure
liver problems including liver failure
kidney problems including kidney failure
low red blood cells (anemia)
Reference ID: 3928095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
life-threatening skin reactions
life-threatening allergic reactions
Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea,
vomiting, and dizziness.
Get emergency help right away if you get any of the following symptoms:
shortness of breath or trouble breathing
chest pain
weakness in one part or side of your body
slurred speech
swelling of the face or throat
Stop taking your NSAID and call your healthcare provider right away if you get any of the following
symptoms:
nausea
more tired or weaker than usual
diarrhea
itching
your skin or eyes look yellow
indigestion or stomach pain
flu-like symptoms
vomit blood
there is blood in your bowel movement or
it is black and sticky like tar
unusual weight gain
skin rash or blisters with fever
swelling of the arms, legs, hands and
feet
If you take too much of your NSAID, call your healthcare provider or get medical help right away.
These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or
pharmacist about NSAIDs.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Other information about NSAIDs
Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in
the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare
provider before using over-the-counter NSAIDs for more than 10 days.
General information about the safe and effective use of NSAIDs
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the
same symptoms that you have. It may harm them.
If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist
or healthcare provider for information about NSAIDs that is written for health professionals.
Manufactured for and Distributed by:
Iroko Pharmaceuticals, LLC
One Kew Place
150 Rouse Boulevard
Philadelphia, PA 19112
For more information, go to www.iroko.com or call 1-877-757-0676
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued or Revised: May 2016
Reference ID: 3928095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
1
DITROPAN®
(oxybutynin chloride)
Tablets and Syrup
DESCRIPTION
Each scored biconvex, engraved blue DITROPAN (oxybutynin chloride) Tablet contains
5 mg of oxybutynin chloride. Each 5 mL of DITROPAN Syrup contains 5 mg of
oxybutynin chloride. Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-
butynyl phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin
chloride is C22H31NO3•HCl. The structural formula appears below:
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It is
readily soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN Tablets
Also contains: calcium stearate, FD&C Blue #1 Lake, lactose, and microcrystalline
cellulose.
DITROPAN Syrup
Also contains: citric acid, FD&C Green #3, glycerin, methylparaben, flavor, sodium
citrate, sorbitol, sucrose, and water.
DITROPAN Tablets and Syrup are for oral administration.
Therapeutic Category: Antispasmodic, anticholinergic.
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits
the muscarinic action of acetylcholine on smooth muscle. Oxybutynin chloride exhibits
only one fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but
four to ten times the antispasmodic activity. No blocking effects occur at skeletal
neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions
characterized by involuntary bladder contractions, cystometric studies have
demonstrated that oxybutynin chloride increases bladder (vesical) capacity, diminishes
the frequency of uninhibited contractions of the detrusor muscle, and delays the initial
desire to void. Oxybutynin chloride thus decreases urgency and the frequency of both
incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominately in the R-isomer. A metabolite,
desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in vitro
studies.
Pharmacokinetics
Absorption
Following oral administration of DITROPAN, oxybutynin is rapidly absorbed achieving
Cmax within an hour, following which plasma concentration decreases with an effective
half-life of approximately 2 to 3 hours. The absolute bioavailability of oxybutynin is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
2
reported to be about 6% (range 1.6 to 10.9%) for both the tablet and syrup. Wide
interindividual variation in pharmacokinetic parameters is evident following oral
administration of oxybutynin.
The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in
Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar in
shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters
Following Three doses of Ditropan 5 mg administered every 8 hours (n=23)
Parameters (units)
R-oxybutynin
S-oxybutynin
Cmax (ng/mL)
3.6 (2.2)
7.8 (4.1)
Tmax (h)
0.89 (0.34)
0.65 (0.32)
AUCt (ng⋅h/mL)
22.6 (11.3)
35.0 (17.3)
AUCinf (ng⋅h/mL)
24.3 (12.3)
37.3 (18.7)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0
4
8
12
16
20
24
Time (h)
Mean Plasma R-Oxybutynin Concentration
(ng/mL)
Oxybutynin 5 mg TID
Figure 1. Mean R-oxybutynin plasma concentrations following three doses of
DITROPAN 5 mg administered every 8 hours for 1 day in 23 healthy adult volunteers
DITROPAN steady-state pharmacokinetics was also studied in 23 pediatric patients
with detrusor overactivity associated with a neurological condition (e.g., spina bifida).
These pediatric patients were on Ditropan tablets (n=11) with total daily dose ranging
from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg) or Ditropan syrup (n=12) with total daily dose
ranging from 5 mg to 22.5 mg (0.26 to 0.75 mg/kg). Overall, most patients (86.9%) were
taking a total daily Ditropan dose between 10 mg and 15 mg. Sparse sampling
technique was used to obtain serum samples. When all available data are normalized to
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NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
3
an equivalent of 5 mg twice daily Ditropan, the mean pharmacokinetic parameters
derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in
Table 2a (for tablet) and Table 2b (for syrup). The plasma-time concentration profile for
R- and S-oxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin
when all available data are normalized to an equivalent of 5 mg twice daily.
Table 2a
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters
In Children Aged 5-15
Following Administration of 7.5 mg to 15 mg Total Daily Dose of Ditropan Tablets (N=11)
All Available Data Normalized to An Equivalent of Ditropan Tablets 5 mg BID or TID at Steady State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax*(ng/mL)
6.1± 3.2
10.1 ± 7.5
55.4 ± 17.9
28.2 ± 10.0
Tmax (hr)
1.0
1.0
2.0
2.0
AUC**
(ng.hr/mL)
19.8 ± 7.4
28.4 ± 12.7
238.8 ± 77.6
119.5 ± 50.7
*Reflects Cmax for pooled data
**AUC0-end of dosing interval
Table 2b
Mean ± SD R- and S-oxybutynin and R- and S-desethyloxybutynin Pharmacokinetic Parameters
In Children Aged 5-15
Following Administration of 5 mg to 22.5 mg Total Daily Dose of Ditropan Syrup (N=12)
All Available Data Normalized to An Equivalent of Ditropan Syrup 5 mg BID or TID at Steady State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax* (ng/mL)
5.7 ± 6.2
7.3 ± 7.3
54.2 ± 34.0
27.8 ± 20.7
Tmax (hr)
1.0
1.0
1.0
1.0
AUC**
(ng.hr/mL)
16.3 ± 17.1
20.2 ± 20.8
209.1 ± 174.2
99.1 ± 87.5
*Reflects Cmax for pooled data
**AUC0-end of dosing interval
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NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
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4
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Time (h)
Mean R-Oxybutynin Plasma
Concentration (ng/mL)
Ditropan Syrup 5 mg
Ditropan IR Tablet 5 mg
Figure 2. Mean steady-state (±SD) R-oxybutynin plasma concentrations following administration
of total daily Ditropan dose of 5 mg to 30 mg (0.21 mg/kg to 0.77 mg/kg) in children 5-15 years of
age. – Plot represents all available data normalized to the equivalent of Ditropan 5 mg BID or
TID at steady state
Food effects
Data in the literature suggests that oxybutynin solution co-administered with food
resulted in a slight delay in absorption and an increase in its bioavailability by 25%
(n=18).1
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous or
oral administration. The volume of distribution is 193 L after intravenous administration
of 5 mg oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems,
particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products
include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and
desethyloxybutynin, which is pharmacologically active.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the
administered dose excreted unchanged in the urine. Also, less than 0.1% of the
administered dose is excreted as the metabolite desethyloxybutynin.
Clinical Studies
DITROPAN was well tolerated in patients administered the drug in controlled studies of
30 days’ duration and in uncontrolled studies in which some of the patients received the
drug for 2 years.
1 Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal subjects. Pharm Res.
1991; 8 (Suppl.): S-320
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NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
5
INDICATIONS AND USAGE
DITROPAN (oxybutynin chloride) is indicated for the relief of symptoms of bladder
instability associated with voiding in patients with uninhibited neurogenic or reflex
neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence,
dysuria).
CONTRAINDICATIONS
DITROPAN is contraindicated in patients with urinary retention, gastric retention and
other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle
glaucoma and in patients who are at risk for these conditions.
DITROPAN is also contraindicated in patients who have demonstrated hypersensitivity
to the drug substance or other components of the product.
PRECAUTIONS
General
DITROPAN should be used with caution in the frail elderly, in patients with hepatic or
renal impairment, and in patients with myasthenia gravis.
DITROPAN may aggravate the symptoms of hyperthyroidism, coronary heart disease,
congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia, hypertension,
myasthenia gravis, and prostatic hypertrophy.
Urinary Retention
DITROPAN should be administered with caution to patients with clinically significant
bladder outflow obstruction because of the risk of urinary retention (See
CONTRAINDICATIONS).
Gastrointestinal Disorders
DITROPAN should be administered with caution to patients with gastrointestinal
obstructive disorders because of the risk of gastric retention (see
CONTRAINDICATIONS).
Administration of DITROPAN to patients with ulcerative colitis may suppress intestinal
motility to the point of producing a paralytic ileus and precipitate or aggravate toxic
megacolon, a serious complication of the disease.
DITROPAN, like other anticholinergic drugs, may decrease gastrointestinal motility and
should be used with caution in patients with conditions such as ulcerative colitis, and
intestinal atony.
DITROPAN should be used with caution in patients who have gastroesophageal reflux
and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or
exacerbate esophagitis.
Information for Patients
Patients should be informed that heat prostration (fever and heat stroke due to
decreased sweating) can occur when anticholinergics such as oxybutynin chloride are
administered in the presence of high environmental temperature.
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6
Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence) or blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by
anticholinergic agents such as oxybutynin.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other agents
which produce dry mouth, constipation, somnolence (drowsiness), and/or other
anticholinergic-like effects may increase the frequency and/or severity of such effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. This may be
of concern for drugs with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 3-4 fold higher
when DITROPAN (oxybutynin chloride) was administered with ketoconazole, a potent
CYP3A4 inhibitor.
Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic
agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin
and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax
and AUC). The clinical relevance of such potential interactions is not known. Caution
should be used when such drugs are co-administered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and 160 mg/kg/day
showed no evidence of carcinogenicity. These doses are approximately 6, 25, and 50
times the maximum human exposure, based on surface area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella
typhimurium test systems.
Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse
have shown no definite evidence of impaired fertility.
Pregnancy
Category B. Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat,
and mouse have shown no definite evidence of impaired fertility or harm to the animal
fetus. The safety of DITROPAN administered to women who are or who may become
pregnant has not been established. Therefore, DITROPAN should not be given to
pregnant women unless, in the judgment of the physician, the probable clinical benefits
outweigh the possible hazards.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when DITROPAN is administered
to a nursing woman.
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NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
7
Pediatric Use
The safety and efficacy of DITROPAN (oxybutynin chloride) administration have been
demonstrated for pediatric patients 5 years of age and older (see DOSAGE AND
ADMINISTRATION).
The safety and efficacy of Ditropan Tablets and Ditropan Syrup were studied in 30 and
in 26 children, respectively, in a 24-week, open-label trial. Patients were aged 5-15
years, all had symptoms of detrusor overactivity in association with a neurological
condition (e.g., spina bifida), all used clean intermittent catheterization, and all were
current users of oxybutynin chloride. Study results demonstrated that the administration
of DITROPAN was associated with improvement in clinical and urodynamic parameters.
At total daily doses ranging from 5 mg to 15 mg, treatment with Ditropan Tablets was
associated with an increase from baseline in mean urine volume per catheterization from
122 mL to 145 mL, an increase from baseline in mean urine volume after morning
awakening from 148 mL to 168 mL, and an increase from baseline in the mean
percentage of catheterizations without a leaking episode from 43% to 61%. Urodynamic
results in these patients were consistent with the clinical results. Treatment with
Ditropan Tablets was associated with an increase from baseline in maximum
cystometric capacity from 230 mL to 279 mL, a decrease from baseline in mean detrusor
pressure at maximum cystometric capacity from 36 cm H20 to 33 cm H20, and a
reduction in the percentage of patients demonstrating uninhibited detrusor contractions
(of at least 15 cm H20) from 39% to 20%.
At total daily doses ranging from 5 mg to 30 mg, treatment with Ditropan Syrup was
associated with an increase from baseline in mean urine volume per catheterization from
113 mL to 133 mL, an increase from baseline in mean urine volume after morning
awakening from 143 mL to 165 mL, and an increase from baseline in the mean
percentage of catheterizations without a leaking episode from 34% to 63%. Urodynamic
results were consistent with these clinical results. Treatment with Ditropan Syrup was
associated with an increase from baseline in maximum cystometric capacity from 192
mL to 294 mL, a decrease from baseline in mean detrusor pressure at maximum
cystometric capacity from 46 cm H20 to 37 cm H20, and a reduction in the percentage of
patients demonstrating uninhibited detrusor contractions (of at least 15 cm H20) from
67% to 28%.
As there is insufficient clinical data for pediatric populations under age 5, DITROPAN is
not recommended for this age group.
Geriatric Use
Clinical studies of DITROPAN did not include sufficient numbers of subjects age 65 and
over to determine whether they respond differently from younger patients. Other
reported clinical experience has not identified differences in responses between healthy
elderly and younger patients; however, a lower initial starting dose of 2.5 mg given 2 or 3
times a day has been recommended for the frail elderly due to a prolongation of the
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NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
8
elimination half-life from 2-3 hours to 5 hours.2,3,4 In general, dose selection for an elderly
patient should be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal or cardiac function, and of
concomitant disease or other drug therapy.
ADVERSE REACTIONS
The safety and efficacy of DITROPAN (oxybutynin chloride) was evaluated in a total of
199 patients in three clinical trials comparing DITROPAN with DITROPAN XL (see Table
3). These participants were treated with DITROPAN 5-20 mg/day for up to 6 weeks.
Table 3 shows the incidence of adverse events judged by investigator to be at least
possibly related to treatment and reported by at least 5% of patients.
Table 3
Incidence (%) of Adverse Events Reported by > 5% of Patients
Using DITROPAN (5-20 mg/day)
Body System
Adverse Event
DITROPAN
(5-20
mg/day)
(n=199)
General
Abdominal pain
Headache
6.5%
6.0%
Digestive
Dry mouth
Constipation
Nausea
Dyspepsia
Diarrhea
71.4%
12.6%
10.1%
7.0%
5.0%
Nervous
Dizziness
Somnolence
15.6%
12.6%
Special senses
Blurred vision
9.0%
Urogenital
Urination impaired
Post void residuals increase
Urinary tract infection
10.6%
5.0%
5.0%
The most common adverse events reported by patients receiving DITROPAN 5-20
mg/day were the expected side effects of anticholinergic agents. The incidence of dry
mouth was dose-related.
In addition, the following adverse events were reported by 2 to <5% of patients using
DITROPAN (5-20 mg/day) in all studies. General: asthenia, dry nasal and sinus mucous
2 Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application
to pharmacokinetic studies in young, elderly and frail elderly volunteers. Xenobiotica. 1992; 22 (7): 859-
869.
3 Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in Geriatric Patients. J. Urol.
1988; 140: 47-50
4 Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and Pharmacokinetic Properties, and its
Therapeutic Use in Detrusor Instability. Drugs & Aging. 1995; 6 (3): 243-262.
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9
membranes; Cardiovascular: palpitation; Metabolic and Nutritional System: peripheral
edema; Nervous System: insomnia, nervousness, confusion; Skin: dry skin; Special
Senses: dry eyes, taste perversion.
Other adverse events that have been reported include: tachycardia, hallucinations,
cycloplegia, mydriasis, impotence, suppression of lactation, vasodilatation, rash,
decreased gastrointestinal motility, flatulence, urinary retention, convulsions and
decreased sweating.
OVERDOSAGE
Treatment should be symptomatic and supportive. Activated charcoal as well as a
cathartic may be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects
including central nervous system excitation (e.g., restlessness, tremor, irritability,
convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac arrhythmia,
vomiting, and urinary retention. Other symptoms may include hypotension or
hypertension, respiratory failure, paralysis, and coma.
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in
a 13 year old boy who experienced memory loss, and a 34 year old woman who
developed stupor, followed by disorientation and agitation on awakening, dilated pupils,
dry skin, cardiac arrhythmia, and retention of urine. Both patients fully recovered with
symptomatic treatment.
DOSAGE AND ADMINISTRATION
Tablets
Adults: The usual dose is one 5-mg tablet two to three times a day. The maximum
recommended dose is one 5-mg tablet four times a day. A lower starting dose of 2.5 mg
two or three times a day is recommended for the frail elderly.
Pediatric patients over 5 years of age: The usual dose is one 5-mg tablet two times a
day. The maximum recommended dose is one 5-mg tablet three times a day.
Syrup
Adults: The usual dose is one teaspoon (5 mg/5 mL) syrup two to three times a day.
The maximum recommended dose is one teaspoon (5 mg/5 mL) syrup four times a day.
A lower starting dose of 2.5 mg two or three times a day is recommended for the frail
elderly.
Pediatric patients over 5 years of age: The usual dose is one teaspoon (5 mg/5 mL)
syrup two times a day. The maximum recommended dose is one teaspoon (5 mg/5mL)
syrup three times a day.
HOW SUPPLIED
DITROPAN (oxybutynin chloride) Tablets are supplied in bottles of 100 tablets (NDC
17314-9200-1). Blue scored tablets (5 mg) are engraved with DITROPAN on one side
with 92 and 00, separated by a horizontal score, on the other side.
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10
DITROPAN Syrup (5 mg/5 mL) is supplied in bottles of 16 fluid ounces (473 mL) (NDC
17314-9201-4).
Pharmacist: Dispense in tight, light-resistant container as defined in the USP.
Store at controlled room temperature (59-86°F).
Rx ONLY
Manufactured by Aventis Pharmaceuticals, Inc., Kansas City, MO 64137
Distributed and Marketed by Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ 08869.
Edition: 03/03
50017115
Placeholder for Ortho-
McNeil Pharmaceutical,
Inc. Logo
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
1
DITROPAN XL
(oxybutynin chloride)
Extended Release Tablets
DESCRIPTION
DITROPAN XL® (oxybutynin chloride) is an antispasmodic, anticholinergic agent. Each
DITROPAN XL Extended Release Tablet contains 5 mg, 10 mg or 15 mg of oxybutynin chloride
USP, formulated as a once-a-day controlled-release tablet for oral administration. Oxybutynin
chloride is administered as a racemate of R- and S- enantiomers.
Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-butynyl
phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin chloride is
C22H31NO3 • HCl.
Its structural formula is:
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It is readily
soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN XL also contains the following inert ingredients: cellulose acetate, hydroxypropyl
methylcellulose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, synthetic
iron oxides, titanium dioxide, polysorbate 80, sodium chloride, and butylated hydroxytoluene.
System Components and Performance
DITROPAN XL uses osmotic pressure to deliver oxybutynin chloride at a controlled rate over
approximately 24 hours. The system, which resembles a conventional tablet in appearance,
comprises an osmotically active bilayer core surrounded by a semipermeable membrane. The
bilayer core is composed of a drug layer containing the drug and excipients, and a push layer
containing osmotically active components. There is a precision-laser drilled orifice in the
semipermeable membrane on the drug-layer side of the tablet. In an aqueous environment, such
as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing
the drug to go into suspension and the push layer to expand. This expansion pushes the
suspended drug out through the orifice. The semipermeable membrane controls the rate at
which water permeates into the tablet core, which in turn controls the rate of drug delivery. The
controlled rate of drug delivery into the gastrointestinal lumen is thus independent of pH or
gastrointestinal motility. The function of DITROPAN XL depends on the existence of an osmotic
gradient between the contents of the bilayer core and the fluid in the gastrointestinal tract. Since
the osmotic gradient remains constant, drug delivery remains essentially constant. The
biologically inert components of the tablet remain intact during gastrointestinal transit and are
eliminated in the feces as an insoluble shell.
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
2
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits the
muscarinic action of acetylcholine on smooth muscle. Oxybutynin chloride exhibits only one-fifth
of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the
antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or
autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions characterized by
involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin
increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the
detrusor muscle, and delays the initial desire to void. Oxybutynin thus decreases urgency and
the frequency of both incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominantly in the R-isomer. A metabolite, desethyloxybutynin,
has pharmacological activity similar to that of oxybutynin in in vitro studies.
Pharmacokinetics
Absorption
Following the first dose of DITROPAN XL® (oxybutynin chloride), oxybutynin plasma
concentrations rise for 4 to 6 hours; thereafter steady concentrations are maintained for up to 24
hours, minimizing fluctuations between peak and trough concentrations associated with
oxybutynin.
The relative bioavailabilities of R- and S-oxybutynin from DITROPAN XL are 156% and 187%,
respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R- and S-
oxybutynin are summarized in Table 1. The plasma concentration-time profiles for R- and S-
oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters
Following a Single Dose of DITROPAN XL 10 mg (n=43)
Parameters (units)
R-Oxybutynin
S-Oxybutynin
Cmax (ng/mL)
1.0
(0.6)
1.8
(1.0)
Tmax (h)
12.7
(5.4)
11.8
(5.3)
t1/2 (h)
13.2
(6.2)
12.4
(6.1)
AUC(0-48) (ng⋅h/mL)
18.4
(10.3)
34.2
(16.9)
AUCinf (ng⋅h/mL)
21.3
(12.2)
39.5
(21.2)
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
3
Figure 1. Mean R-oxybutynin plasma concentrations following a single dose of DITROPAN XL 10 mg and oxybutynin 5 mg
administered every 8 hours (n=23 for each treatment).
Steady-state oxybutynin plasma concentrations are achieved by Day 3 of repeated DITROPAN
XL® (oxybutynin chloride) dosing, with no observed drug accumulation or change in oxybutynin
and desethyloxybutynin pharmacokinetic parameters.
DITROPAN XL steady-state pharmacokinetics was studied in 19 children aged 5-15 years with
detrusor overactivity associated with a neurological condition (e.g. spina bifida). The children
were on DITROPAN XL total daily dose ranging from 5 to 20 mg (0.10 to 0.77 mg/kg). Sparse
sampling technique was used to obtain serum samples. When all available data are normalized
to an equivalent of 5mg per day Ditropan XL, the mean pharmacokinetic parameters derived for
R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 2. The plasma-
time concentration profiles for R- and S-oxybutynin are similar in shape; Figure 2 shows the
profile for R-oxybutynin when all available data are normalized to an equivalent of 5 mg per day.
Table 2
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged 5-15
Following Administration of 5 to 20mg Ditropan XL Once Daily (N=19)
All Available Data Normalized To An Equivalent of Ditropan XL 5 mg Once Daily
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax (ng/mL)
0.7 ± 0.4
1.3 ± 0.8
7.8 ± 3.7
4.2 ± 2.3
Tmax (hr)
5.0
5.0
5.0
5.0
AUC (ng.hr/mL)
12.8 ± 7.0
23.7 ± 14.4
125.1 ± 66.7
73.6 ± 47.7
DITROPAN
XL
10 mg QD
oxybutynin 5 mg TID
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
4
Figure 2. Mean steady state (±SD) R-oxybutynin plasma concentrations following administration of 5 to 20
mg Ditropan XL once daily in children aged 5-15. - Plot represents all available data normalized to an
equivalent of Ditropan XL 5 mg once daily
Food Effects
The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted
conditions.
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous or oral
administration. The volume of distribution is 193 L after intravenous administration of 5 mg
oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly
CYP3A4 found mostly in the liver and gut wall. Its metabolic products include
phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which
is pharmacologically active. Following DITROPAN XL administration, plasma concentrations of
R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed with
oxybutynin.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose
excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted as
the metabolite desethyloxybutynin.
Dose Proportionality
Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC) following
administration of 5-20 mg of DITROPAN XL are dose proportional.
0.0
0.5
1.0
1.5
2.0
0
5
10
15
20
25
Time (hours)
Mean R-Oxybutynin Plasma
Concentration (ng/ml)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
5
Special Populations
Geriatric: The pharmacokinetics of DITROPAN XL were similar in all patients studied (up to 78
years of age).
Pediatric: The pharmacokinetics of DITROPAN XL (oxybutynin chloride) were evaluated in 19
children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g.,
spina bifida). The pharmacokinetics of DITROPAN XL in these pediatric patients were consistent
with those reported for adults (see Tables 1 and 2, and Figures 1 and 2 above).
Gender: There are no significant differences in the pharmacokinetics of oxybutynin in healthy
male and female volunteers following administration of DITROPAN XL.
Race: Available data suggest that there are no significant differences in the pharmacokinetics of
oxybutynin based on race in healthy volunteers following administration of DITROPAN XL.
Renal Insufficiency: There is no experience with the use of DITROPAN XL in patients with renal
insufficiency.
Hepatic Insufficiency: There is no experience with the use of DITROPAN XL in patients with
hepatic insufficiency.
Drug-Drug Interactions: See PRECAUTIONS: Drug Interactions.
Clinical Studies
DITROPAN XL was evaluated for the treatment of patients with overactive bladder with
symptoms of urge urinary incontinence, urgency, and frequency in three controlled studies and
one open label study. The majority of patients were Caucasian (89.0%) and female (91.9%) with
a mean age of 59 years (range, 18 to 98 years). Entry criteria required that patients have urge or
mixed incontinence (with a predominance of urge) as evidenced by ≥ 6 urge incontinence
episodes per week and ≥ 10 micturitions per day. Study 1 was a forced dose escalation design,
whereas the other studies used a dose adjustment design in which each patient’s final dose was
adjusted to a balance between improvement of incontinence symptoms and tolerability of side
effects. Controlled studies included patients known to be responsive to oxybutynin or other
anticholinergic medications, and these patients were maintained on a final dose for up to 2
weeks.
The efficacy results for the three controlled trials are presented in the following tables and
figures.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
7
INDICATIONS AND USAGE
DITROPAN XL® (oxybutynin chloride) is a once-daily controlled-release tablet indicated for the
treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and
frequency.
DITROPAN XL is also indicated in the treatment of pediatric patients aged 6 years and older with
symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida).
CONTRAINDICATIONS
DITROPAN XL is contraindicated in patients with urinary retention, gastric retention and other
severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma and in
patients who are at risk for these conditions.
DITROPAN XL is also contraindicated in patients who have demonstrated hypersensitivity to the
drug substance or other components of the product.
PRECAUTIONS
General
DITROPAN XL should be used with caution in patients with hepatic or renal impairment and in
patients with myasthenia gravis due to the risk of symptom aggravation.
Urinary Retention:
DITROPAN XL should be administered with caution to patients with clinically significant bladder
outflow obstruction because of the risk of urinary retention (see CONTRAINDICATIONS).
Gastrointestinal Disorders:
DITROPAN XL should be administered with caution to patients with gastrointestinal obstructive
disorders because of the risk of gastric retention (see CONTRAINDICATIONS).
DITROPAN XL, like other anticholinergic drugs, may decrease gastrointestinal motility and
should be used with caution in patients with conditions such as ulcerative colitis and intestinal
atony.
DITROPAN XL should be used with caution in patients who have gastroesophageal reflux and/or
who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate
esophagitis.
As with any other nondeformable material, caution should be used when administering
DITROPAN XL to patients with preexisting severe gastrointestinal narrowing (pathologic or
iatrogenic). There have been rare reports of obstructive symptoms in patients with known
strictures in association with the ingestion of other drugs in nondeformable controlled-release
formulations.
Information for Patients
Patients should be informed that heat prostration (fever and heat stroke due to decreased
sweating) can occur when anticholinergics such as oxybutynin chloride are administered in the
presence of high environmental temperature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
8
Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence) or
blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic
agents such as oxybutynin.
Patients should be informed that DITROPAN XL® (oxybutynin chloride) should be swallowed
whole with the aid of liquids. Patients should not chew, divide, or crush tablets. The medication
is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The
tablet shell is eliminated from the body; patients should not be concerned if they occasionally
notice in their stool something that looks like a tablet.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which
produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like
effects may increase the frequency and/or severity of such effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly administered
drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs
with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when
DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors
of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and
miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter
oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of
such potential interactions is not known. Caution should be used when such drugs are co-
administered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80 and 160 mg/kg/day showed
no evidence of carcinogenicity. These doses are approximately 6, 25 and 50 times the maximum
human exposure, based on surface area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae, and Salmonella
typhimurium test systems.
Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no
definite evidence of impaired fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category B
Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no
definite evidence of impaired fertility or harm to the animal fetus. The safety of DITROPAN XL
administration to women who are or who may become pregnant has not been established.
Therefore, DITROPAN XL should not be given to pregnant women unless, in the judgment of the
physician, the probable clinical benefits outweigh the possible hazards.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
9
Nursing Mothers
It is not known whether oxybutynin is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when DITROPAN XL® (oxybutynin chloride) is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of DITROPAN XL were studied in 60 children in a 24-week, open-label
trial. Patients were aged 6-15 years, all had symptoms of detrusor overactivity in association with
a neurological condition (e.g., spina bifida), all used clean intermittent catheterization, and all
were current users of oxybutynin chloride. Study results demonstrated that administration of
DITROPAN XL 5 to 20 mg/day was associated with an increase from baseline in mean urine
volume per catheterization from 108 mL to 136 mL, an increase from baseline in mean urine
volume after morning awakening from 148 mL to 189 mL, and an increase from baseline in the
mean percentage of catheterizations without a leaking episode from 34% to 51%.
Urodynamic results were consistent with clinical results. Administration of DITROPAN XL resulted
in an increase from baseline in mean maximum cystometric capacity from 185 mL to 254 mL, a
decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 44 cm
H2O to 33 cm H2O, and a reduction in the percentage of patients demonstrating uninhibited
detrusor contractions (of at least 15 cm H2O) from 60% to 28%.
DITROPAN XL is not recommended in pediatric patients who can not swallow the tablet whole
without chewing, dividing, or crushing, or in children under the age of 6 (see DOSAGE AND
ADMINISTRATION).
Geriatric Use
The rate and severity of anticholinergic effects reported by patients less than 65 years old and
those 65 years and older were similar (See CLINICAL PHARMACOLOGY, Pharmacokinetics,
Special Populations: Gender).
ADVERSE REACTIONS
Adverse Events with DITROPAN XL®
The safety and efficacy of DITROPAN XL was evaluated in a total of 580 participants who
received DITROPAN XL in clinical trials (429 patients, 151 healthy volunteers). These
participants were treated with 5-30 mg/day for up to 4.5 months. Safety information is provided
for 429 patients from three controlled clinical studies and one open label study (Table 3). The
adverse events are reported regardless of causality.
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
10
Table 3
Incidence (%) of Adverse Events Reported by ≥≥≥≥ 5% of Patients
Using DITROPAN XL (5-30 mg/day)
DITROPAN XL
Body System
Adverse Event
5-30 mg/day
(n=429)
General
headache
9.8
asthenia
6.8
pain
6.8
Digestive
dry mouth
60.8
constipation
13.1
diarrhea
9.1
nausea
8.9
dyspepsia
6.8
Nervous
somnolence
11.9
dizziness
6.3
Respiratory
rhinitis
5.6
Special senses
blurred vision
7.7
dry eyes
6.1
Urogenital
urinary tract infection
5.1
The most common adverse events reported by patients receiving 5-30 mg/day
DITROPAN XL® were the expected side effects of anticholinergic agents. The incidence of dry
mouth was dose-related.
The discontinuation rate for all adverse events was 6.8%. The most frequent adverse event
causing early discontinuation of study medication was nausea (1.9%), while discontinuation due
to dry mouth was 1.2%.
In addition, the following adverse events were reported by 2 to < 5% of patients using DITROPAN
XL (oxybutynin chloride) (5-30 mg/day) in all studies. General: abdominal pain, dry nasal and
sinus mucous membranes, accidental injury, back pain, flu syndrome; Cardiovascular:
hypertension, palpitation, vasodilatation; Digestive: flatulence, gastroesophageal reflux;
Musculoskeletal: arthritis; Nervous: insomnia, nervousness, confusion; Respiratory: upper
respiratory tract infection, cough, sinusitis, bronchitis, pharyngitis; Skin: dry skin, rash; Urogenital:
impaired urination (hesitancy), increased post void residual volume, urinary retention, cystitis.
Additional rare adverse events reported from worldwide post-marketing experience with
DITROPAN XL include: peripheral edema, cardiac arrhythmia, tachycardia, hallucinations,
convulsions, and impotence.
Additional adverse events reported with some other oxybutynin chloride formulations include:
cycloplegia, mydriasis, and suppression of lactation.
OVERDOSAGE
The continuous release of oxybutynin from DITROPAN XL (oxybutynin chloride) should be
considered in the treatment of overdosage. Patients should be monitored for at least 24 hours.
Treatment should be symptomatic and supportive. Activated charcoal as well as a cathartic may
be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects including
central nervous system excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and
urinary retention.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
11
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in a 13
year old boy who experienced memory loss, and a 34 year old woman who developed stupor,
followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia,
and retention of urine. Both patients fully recovered with symptomatic treatment.
DOSAGE AND ADMINISTRATION
DITROPAN XL® must be swallowed whole with the aid of liquids, and must not be chewed,
divided, or crushed.
DITROPAN XL® may be administered with or without food.
Adults: The recommended starting dose of DITROPAN XL® is 5 mg once daily. Dosage may be
adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of
30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals.
Pediatric patients aged 6 years of age and older: The recommended starting dose of DITROPAN
XL is 5 mg once daily. Dosage may be adjusted in 5-mg increments to achieve a balance of
efficacy and tolerability (up to a maximum of 20 mg/day).
HOW SUPPLIED
DITROPAN XL® (oxybutynin chloride) Extended Release Tablets are available in three dosage
strengths, 5 mg (pale yellow), 10 mg (pink) and 15 mg (gray) and are imprinted with
“5 XL”, “10 XL” or “15 XL”. DITROPAN XL® (oxybutynin chloride) Extended Release Tablets are
supplied in bottles of 100 tablets.
5 mg
100 count bottle
NDC 17314-8500-1
10 mg
100 count bottle
NDC 17314-8501-1
15 mg
100 count bottle
NDC 17314-8502-1
Storage
Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room
Temperature]. Protect from moisture and humidity.
Rx only
For more information call 1-888-395-1232 or visit www.DitropanXL.com
Manufactured by
ALZA Corporation, Mountain View, CA 94043.
An ALZA OROS
Technology Product
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
12
DITROPAN XL and OROS are registered trademarks of ALZA Corporation.
Distributed and Marketed by
Ortho-McNeil Pharmaceuticals, Inc., Raritan, NJ 08869.
00096532
Edition: 3/03
Placeholder for Ortho-McNeil
Pharmaceuticals, Inc. Logo
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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11,184
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NDA 18-202/S-021
Page 3
Cytadren® Tablets
aminoglutethimide tablets USP
Rx only
Prescribing Information
DESCRIPTION
Cytadren, aminoglutethimide tablets USP, is an inhibitor of adrenocortical steroid synthesis, available
as 250-mg tablets for oral administration. Its chemical name is 3-(4-aminophenyl)-3-ethyl-2,6-
piperidinedione, and its structural formula is
Aminoglutethimide USP is a fine, white or creamy white, crystalline powder. It is very slightly
soluble in water, and readily soluble in most organic solvents. It forms water- soluble salts with strong
acids. Its molecular weight is 232.28.
Inactive Ingredients. Cellulose compounds, colloidal silicon dioxide, starch, stearic acid, and
talc.
CLINICAL PHARMACOLOGY
Cytadren inhibits the enzymatic conversion of cholesterol to ∆5-pregnenolone, resulting in a decrease
in the production of adrenal glucocorticoids, mineralocorticoids, estrogens, and androgens.
Cytadren blocks several other steps in steroid synthesis, including the C-11, C-18, and C-21
hydroxylations and the hydroxylations required for the aromatization of androgens to estrogens,
mediated through the binding of Cytadren to cytochrome P-450 complexes.
A decrease in adrenal secretion of cortisol is followed by an increased secretion of pituitary
adrenocorticotropic hormone (ACTH), which will overcome the blockade of adrenocortical steroid
synthesis by Cytadren. The compensatory increase in ACTH secretion can be suppressed by the
simultaneous administration of hydrocortisone. Since Cytadren increases the rate of metabolism of
dexamethasone but not that of hydrocortisone, the latter is preferred as the adrenal glucocorticoid
replacement.
This label may not be the latest approved by FDA.
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NDA 18-202/S-021
Page 4
Although Cytadren inhibits the synthesis of thyroxine by the thyroid gland, the compensatory
increase in thyroid-stimulating hormone (TSH) is frequently of sufficient magnitude to overcome the
inhibition of thyroid synthesis due to Cytadren. In spite of an increase in TSH, Cytadren has not been
associated with increased prolactin secretion.
Note: Cytadren was marketed previously as an anticonvulsant but was withdrawn from
marketing for that indication in 1966 because of the effects on the adrenal gland.
Pharmacokinetics
Cytadren is rapidly and completely absorbed after oral administration. In 6 healthy male volunteers,
maximum plasma levels of Cytadren averaged 5.9 µg/mL at a median of 1.5 hours after ingestion of
two 250-mg tablets. The bioavailability of tablets is equivalent to equal doses given as a solution.
After ingestion of a single oral dose, 34%-54% is excreted in the urine as unchanged drug during the
first 48 hours, and an additional fraction as the N-acetyl derivative.
The half-life of Cytadren in normal volunteers given single oral doses averaged 12.5 ± 1.6
hours.
Upon withdrawal of therapy with Cytadren, the ability of the adrenal glands to synthesize
steroid returns, usually within 72 hours.
INDICATIONS AND USAGE
Cytadren is indicated for the suppression of adrenal function in selected patients with Cushing’s
syndrome. Morning levels of plasma cortisol in patients with adrenal carcinoma and ectopic ACTH-
producing tumors were reduced on the average to about one half of the pretreatment levels, and in
patients with adrenal hyperplasia to about two thirds of the pretreatment levels, during 1-3 months of
therapy with Cytadren. Data available from the few patients with adrenal adenoma suggest similar
reductions in plasma cortisol levels. Measurements of plasma cortisol showed reductions to at least
50% of baseline or to normal levels in one third or more of the patients studied, depending on
diagnostic groups and time of measurement.
Because Cytadren does not affect the underlying disease process, it is used primarily as an
interim measure until more definitive therapy such as surgery can be undertaken or in cases where such
therapy is not appropriate. Only small numbers of patients have been treated for longer than 3 months.
A decreased effect or “escape phenomenon” seems to occur more frequently in patients with pituitary-
dependent Cushing’s syndrome, probably because of increasing ACTH levels in response to
decreasing glucocorticoid levels.
Cytadren should be used only in those patients who are responsive to treatment.
CONTRAINDICATIONS
Cytadren is contraindicated in those patients with serious forms, and/or more severe manifestations, of
hypersensitivity to glutethimide or aminoglutethimide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-202/S-021
Page 5
WARNINGS
Cytadren may cause adrenocortical hypofunction, especially under conditions of stress, such as
surgery, trauma, or acute illness. Patients should be carefully monitored and given hydrocortisone and
mineralocorticoid supplements as indicated. Dexamethasone should not be used. (See
PRECAUTIONS, Drug Interactions.)
Cytadren also may suppress aldosterone production by the adrenal cortex and may cause
orthostatic or persistent hypotension. The blood pressure should be monitored in all patients at
appropriate intervals. Patients should be advised of the possible occurrence of weakness and dizziness
as symptoms of hypotension, and of measures to be taken should they occur.
The effects of Cytadren may be potentiated if it is taken in combination with alcohol.
Cytadren can cause fetal harm when administered to a pregnant woman. In the earlier
experience with the drug in about 5000 patients, two cases of pseudohermaphroditism were reported in
female infants whose mothers were treated with Cytadren and concomitant anticonvulsants. Normal
pregnancies have also occurred in patients treated with Cytadren.
When administered to rats at doses 1/2 and 1 1/4 times the maximum daily human dose,
Cytadren caused a decrease in fetal implantation, an increase in fetal deaths, and a variety of
teratogenic effects. The compound also caused pseudohermaphroditism in rats treated with
approximately 3 times the maximum daily human dose. If this drug must be used during pregnancy, or
if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential
hazard to the fetus.
PRECAUTIONS
General
This drug should be administered only by physicians familiar with its use and hazards. Therapy should
be initiated in a hospital. (See DOSAGE AND ADMINISTRATION.)
Information for Patients
Patients should be warned that drowsiness may occur and that they should not drive, operate
potentially dangerous machinery, or engage in other activities that may become hazardous because of
decreased alertness.
Patients should also be warned of the possibility of hypotension and its symptoms (see
WARNINGS).
Laboratory Tests
Hypothyroidism may occur in association with Cytadren; hence, appropriate clinical observations
should be made and laboratory studies of thyroid function performed as indicated. Supplementary
thyroid hormone may be required.
Hematologic abnormalities in patients receiving Cytadren have been reported (see ADVERSE
REACTIONS). Therefore, baseline hematologic studies should be performed, followed by periodic
hematologic evaluation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-202/S-021
Page 6
Since elevations in SGOT, alkaline phosphatase, and bilirubin have been reported, appropriate
clinical observations and regular laboratory studies should be performed before and during therapy.
Serum electrolyte levels should be determined periodically.
Drug Interactions
Cytadren accelerates the metabolism of dexamethasone; therefore, if glucocorticoid replacement is
needed, hydrocortisone should be prescribed.
Aminoglutethimide diminishes the effect of coumarin and warfarin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 2-year carcinogenicity study of Cytadren conducted in rats at doses of 10-60 mg/kg/day
(approximately 0.04 to 0.2 times the maximum daily therapeutic dose based on surface area, mg/m2)
revealed a highly statistically significant dose-related trend in the incidence of benign and malignant
neoplasms of the adrenal cortex and thyroid follicular cells in both sexes. A borderline statistically
significant increase (0.05 level) in ovarian tubular adenomas was observed at 60 mg/kg/day. Urinary
bladder papillomas also showed a statistically significant dose-related trend in males.
Cytadren affects fertility in female rats (see WARNINGS). The relevance of these findings to
humans is not known.
Pregnancy Category D
See WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk and because of the potential for serious adverse reactions in nursing infants from
Cytadren, a decision should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established (see CLINICAL STUDIES IN
CHILDREN).
Geriatric Use
Clinical studies of Cytadren did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Spontaneous post-marketing
adverse event reports and reports from the published literature have not identified obvious differences
in responses between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function,
and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Untoward effects have been reported in about 2 out of 3 patients with Cushing’s syndrome who were
treated for 4 or more weeks with Cytadren as the only adrenocortical suppressant.
This label may not be the latest approved by FDA.
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NDA 18-202/S-021
Page 7
The most frequent and reversible side effects were drowsiness (approximately 1 in 3 patients),
morbilliform skin rash (1 in 6 patients), nausea and anorexia (each approximately 1 in 8 patients), and
dizziness (about 1 in 20 patients). The dizziness was possibly caused by lowered vascular resistance or
orthostasis. These reactions often disappear spontaneously with continued therapy.
Other Effects Observed
Hematologic: Single instances of neutropenia, leukopenia (patient received concomitant o,p'-DDD),
pancytopenia (patient received concomitant 5-fluorouracil), and agranulocytosis occurred in 4 of 27
patients with Cushing’s syndrome caused by adrenal carcinoma who were treated for at least 4 weeks.
In 1 patient with adrenal hyperplasia, hemoglobin levels and hematocrit decreased during the course of
treatment with Cytadren. From the earlier experience with the drug used as an anticonvulsant in 1,214
patients, transient leukopenia was the only hematologic effect and was reported once; Coombs’-
negative hemolytic anemia also occurred once. In approximately 300 patients with nonadrenal
malignancy, 1 in 25 showed some degree of anemia, and 1 in 150 developed pancytopenia during
treatment with Cytadren.
Endocrine: Adrenal insufficiency occurred in about 1 in 30 patients with Cushing’s syndrome
who were treated with Cytadren for 4 or more weeks. This insufficiency tended to involve
glucocorticoids as well as mineralocorticoids. Hypothyroidism is occasionally associated with thyroid
enlargement and may be detected or confirmed by measuring plasma levels of the thyroid hormone.
Masculinization and hirsutism have occasionally occurred in females, as has precocious sexual
development in males.
Central Nervous System: Headache was reported in about 1 in 20 patients.
Cardiovascular: Hypotension, occasionally orthostatic, occurred in 1 in 30 patients receiving
Cytadren. Tachycardia occurred in 1 in 40 patients.
Gastrointestinal and Liver: Vomiting occurred in 1 in 30 patients. Isolated instances of
abnormal findings on liver function tests were reported. Suspected hepatotoxicity occurred in less than
1 in 1000 patients.
Skin: In addition to rash (1 in 6 patients, and often reversible with continued therapy), pruritus
was reported in 1 in 20 patients. These may be allergic or hypersensitive reactions. Urticaria has
occurred rarely.
Miscellaneous: Fever was reported in several patients who were treated with Cytadren for less
than 4 weeks; some of these patients also received other drugs. Myalgia occurred in 1 in 30 patients.
Pulmonary hypersensitivity, including allergic alveolitis and interstitial alveolar infiltrates, has
occurred rarely.
OVERDOSAGE
Acute Toxicity
No deaths due to overdosage with Cytadren have been reported.
The highest known doses that have been survived are 7 g (33-year-old woman), 7.5-10 g (16-
year-old girl), and 10 g (10-year-old boy).
Oral LD50’s (mg/kg): rats, 1800; dogs, >100. Intravenous LD50’s (mg/kg): rats, 156; dogs,
>100.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-202/S-021
Page 8
Signs and Symptoms
An acute overdose with Cytadren may reduce the production of steroids in the adrenal cortex to a
degree that is clinically relevant. The following manifestations may be expected:
Respiratory Function: Respiratory depression, hypoventilation.
Cardiovascular System: Hypotension, hypovolemic shock due to dehydration.
Central Nervous System/Muscles: Somnolence, lethargy, coma, ataxia, dizziness, fatigue.
(Extreme weakness has been reported with divided doses of 3 g daily.)
Gastrointestinal System: Nausea, vomiting.
Renal Function: Loss of sodium and water.
Laboratory Findings: Hyponatremia, hypochloremia, hyperkalemia, hypoglycemia.
The signs and symptoms of acute overdosage with Cytadren may be aggravated or modified if
alcohol, hypnotics, tranquilizers, or tricyclic antidepressants have been taken at the same time.
Treatment
Symptomatic treatment of overdosage is recommended.
Since aminoglutethimide and glutethimide are chemically related, measures that have been
used in successfully removing glutethimide from the body might be useful in removing
aminoglutethimide.
Gastric lavage and unspecified supportive treatment have been employed. Full consciousness
following deep coma was regained 40 hours or less after ingestion of 3 or 4 g without lavage. No
evidence of hematologic, renal, or hepatic effects was subsequently found.
Close monitoring should be provided, and appropriate measures taken to support vital
functions, if necessary.
If deficiency of circulating glucocorticoid develops, an intravenous infusion of a soluble
hydrocortisone preparation (100 mg of hydrocortisone sodium succinate in 500 mL of isotonic sodium
chloride solution) and 50 mL of 40% glucose solution should be given within 3 hours. After the initial
infusion is completed, an intravenous administration of hydrocortisone, 10 mg per hour, should be
continued until the patient is able to take oral cortisone.
If hypovolemia or hypotension occurs, an intravenous administration of norepinephrine, 10 mg,
in 500 mL of isotonic sodium chloride should be administered according to the patient’s needs and
response. After rehydration, 500 mL of plasma or blood should be given for maintenance of sufficient
circulatory volume.
Dialysis may be considered in severe intoxication.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-202/S-021
Page 9
DOSAGE AND ADMINISTRATION
Adults
Treatment should be instituted in a hospital until a stable dosage regimen is achieved. Therapy should
be initiated with 250 mg orally four times daily, preferably at 6-hour intervals. Adrenocortical
response should be followed by careful monitoring of plasma cortisol levels until the desired level of
suppression is achieved. If the level of cortisol suppression is inadequate, the dosage may be increased
in increments of 250 mg daily at intervals of 1-2 weeks to a total daily dose of 2 g. Dose reduction or
temporary discontinuation of therapy may be required in the event of adverse effects, including
extreme drowsiness, severe skin rash, or excessively low cortisol levels. If a skin rash persists for
longer than 5-8 days or becomes severe, the drug should be discontinued. It may be possible to
reinstate therapy at a lower dosage following the disappearance of a mild or moderate rash.
Mineralocorticoid replacement (e.g., fludrocortisone) may be necessary. If glucocorticoid replacement
therapy is needed, 20-30 mg of hydrocortisone orally in the morning will replace endogenous
secretion.
HOW SUPPLIED
Tablets 250 mg — white, round, scored into quarters (imprinted CIBA 24)
Bottles of 100 ........................................................................... NDC 0083-0024-30
Protect from light.
Do not store above 30ºC (86ºF).
Dispense in tight, light-resistant container (USP).
CLINICAL STUDIES IN CHILDREN
Clinical investigations included 9 patients aged 2 1/2 to 16 years; 4 of these were aged 10 or less.
Seven of the patients received other therapies (drugs or irradiation) either with Cytadren or within a
short period before initiation of therapy with Cytadren. Diagnoses included 5 patients with adrenal
carcinoma, 3 with adrenal hyperplasia, and 1 with ectopic ACTH-producing tumor. Duration of
treatment ranged from 3 days to 6 1/2 months. Dosages ranged from 0.375 g to 1.5 g daily. In general,
smaller doses were used for younger patients; for example, a 2 1/2-year- old received 0.5-0.75 g daily,
a 3 1/2-year-old received 0.5 g daily, and all others over 10 years of age received 0.75-1.5 g daily.
Results are difficult to evaluate because of the concomitant therapy, duration of therapy, or inadequate
laboratory documentation. Most patients did show decreases in plasma or urinary steroids at some
time during treatment, but these may have been due to other therapeutic modalities or their
combinations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-202/S-021
Page 10
Manufactured by:
Patheon Whitby Inc.
Whitby Ontario Canada L1N 5Z5
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV:
© 2002 Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/018202s021lbl.pdf', 'application_number': 18202, 'submission_type': 'SUPPL ', 'submission_number': 21}
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BUMEX
Brand of
bumetanide
TABLETS
WARNING
Bumex (bumetanide) is a potent diuretic which, if given in excessive amounts, can lead to a
profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is
required, and dose and dosage schedule have to be adjusted to the individual patient's needs (see
DOSAGE AND ADMINISTRATION).
DESCRIPTION
Bumex (bumetanide) is a loop diuretic, available as scored tablets, 0.5 mg (light green), 1 mg
(yellow) and 2 mg (peach) for oral administration; each tablet also contains lactose, magnesium
stearate, microcrystalline cellulose, cornstarch and talc, with the following dye systems: 0.5 mg-
D&C Yellow No. 10 and FD&C Blue No. 1; 1 mg-D&C Yellow No. 10; 2 mg-red iron oxide.
Chemically, bumetanide is 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid. It is a
practically white powder having a calculated molecular weight of 364.41, and the following
structural formula: Structural Formula
CLINICAL PHARMACOLOGY
Bumex is a loop diuretic with a rapid onset and short duration of action. Pharmacological and
clinical studies have shown that 1 mg Bumex has a diuretic potency equivalent to approximately
40 mg furosemide. The major site of Bumex action is the ascending limb of the loop of Henle.
The mode of action has been determined through various clearance studies in both humans and
experimental animals. Bumex inhibits sodium reabsorption in the ascending limb of the loop of
Henle, as shown by marked reduction of free-water clearance (CH O) during hydration and
tubular free-water reabsorption (T H O) during hydropenia. Reabsorption of chloride in the
ascending limb is also blocked by Bumex, and Bumex is somewhat more chloruretic than
natriuretic.
Potassium excretion is also increased by Bumex, in a dose-related fashion.
Bumex may have an additional action in the proximal tubule. Since phosphate reabsorption
takes place largely in the proximal tubule, phosphaturia during Bumex induced diuresis is
indicative of this additional action. This is further supported by the reduction in the renal
NDA 18225/S-024
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clearance of Bumex by probenecid, associated with diminution in the natriuretic response. This
proximal tubular activity does not seem to be related to an inhibition of carbonic anhydrase.
Bumex does not appear to have a noticeable action on the distal tubule.
Bumex decreases uric acid excretion and increases serum uric acid. Following oral
administration of Bumex the onset of diuresis occurs in 30 to 60 minutes. Peak activity is
reached between 1 and 2 hours. At usual doses (1 mg to 2 mg) diuresis is largely complete
within 4 hours; with higher doses, the diuretic action lasts for 4 to 6 hours. Diuresis starts within
minutes following an intravenous injection and reaches maximum levels within 15 to 30 minutes.
Several pharmacokinetic studies have shown that bumetanide, administered orally or
parenterally, is eliminated rapidly in humans, with a half-life of between 1 and 1½ hours.
Plasma protein-binding is in the range of 94% to 96%.
Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the
administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Urinary and
biliary metabolites identified in this study were formed by oxidation of the N-butyl side chain.
Biliary excretion of Bumex amounted to only 2% of the administered dose.
Pediatric Pharmacology
Elimination of bumetanide appears to be considerably slower in neonatal patients compared with
adults, possibly because of immature renal and hepatobiliary function in this population. Small
pharmacokinetic studies of intravenous bumetanide in preterm and full-term neonates with
respiratory disorders have reported an apparent half-life of approximately 6 hours, with a range
up to 15 hours and a serum clearance ranging from 0.2 to 1.1 mL/min/kg. In a population of
neonates receiving bumetanide for volume overload, mean serum clearance rates were 2.17
mL/min/kg in patients less than 2 months of age and 3.8 mL/min/kg in patients aged 2 to 6
months. Mean serum half-life of bumetanide was 2.5 hours and 1.5 hours in patients aged less
than 2 months and those aged 2 to 6 months, respectively. Elimination half-life decreased
considerably during the first month of life, from a mean of approximately 6 hours at birth to
approximately 2.4 hours at 1 month of age.
In preterm neonates, mean serum concentrations following a single 0.05 mg/kg dose ranged from
126 mcg/L at 1 hour to 57 mcg/L at 8 hours. In another study, mean serum concentrations
following a single 0.05 mg/kg dose were 338 ng/mL at 30 minutes and 176 ng/mL after 4 hours.
A single dose of 0.1 mg/kg produced mean serum levels of 314 ng/mL at 1 hour, and 195 ng/mL
at 6 hours. Mean volume of distribution in neonates and infants has been reported to range from
0.26 L/kg to 0.39 L/kg.
The degree of protein binding of bumetanide in cord sera from healthy neonates was
approximately 97%, suggesting the potential for bilirubin displacement. A study using pooled
sera from critically ill neonates found that bumetanide at concentrations of 0.5 to 50 mcg/mL,
but not 0.25 mcg/mL, caused a linear increase in unbound bilirubin concentrations.
In 56 infants aged 4 days to 6 months, bumetanide doses ranging from 0.005 mg/kg to 0.1 mg/kg
were studied for pharmacodynamic effect. Peak bumetanide excretion rates increased linearly
NDA 18225/S-024
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with increasing doses of drug. Maximal diuretic effect was observed at a bumetanide excretion
rate of about 7 mcg/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses
produced a higher bumetanide excretion rate but no increase in diuretic effect. Urine flow rate
peaked during the first hour after drug administration in 80% of patients and by 3 hours in all
patients.
Geriatric Pharmacology
In a group of ten geriatric subjects between the ages of 65 and 73 years, total bumetanide
clearance was significantly lower (1.8 ± 0.3 mL/min·kg) compared with younger subjects (2.9 ±
0.2 mL/min·kg) after a single oral bumetanide 0.5 mg dose. Maximum plasma concentrations
were higher in geriatric subjects (16.9 ± 1.8 ng/mL) compared with younger subjects (10.3 ± 1.5
ng/mL). Urine flow rate and total excretion of sodium and potassium were increased less in the
geriatric subjects compared with younger subjects, although potassium excretion and fractional
sodium excretion were similar between the two age groups. Nonrenal clearance, bioavailability,
and volume of distribution were not significantly different between the two groups.
INDICATIONS AND USAGE
Bumex is indicated for the treatment of edema associated with congestive heart failure, hepatic
and renal disease, including the nephrotic syndrome.
Almost equal diuretic response occurs after oral and parenteral administration of bumetanide.
Therefore, if impaired gastrointestinal absorption is suspected or oral administration is not
practical, bumetanide should be given by the intramuscular or intravenous route.
Successful treatment with Bumex following instances of allergic reactions to furosemide
suggests a lack of cross-sensitivity.
CONTRAINDICATIONS
Bumex is contraindicated in anuria. Although Bumex can be used to induce diuresis in renal
insufficiency, any marked increase in blood urea nitrogen or creatinine, or the development of
oliguria during therapy of patients with progressive renal disease, is an indication for
discontinuation of treatment with Bumex. Bumex is also contraindicated in patients in hepatic
coma or in states of severe electrolyte depletion until the condition is improved or corrected.
Bumex is contraindicated in patients hypersensitive to this drug.
WARNINGS
Volume and Electrolyte Depletion
The dose of Bumex should be adjusted to the patient's need. Excessive doses or too frequent
administration can lead to profound water loss, electrolyte depletion, dehydration, reduction in
blood volume and circulatory collapse with the possibility of vascular thrombosis and embolism,
particularly in elderly patients.
Hypokalemia
Hypokalemia can occur as a consequence of Bumex administration. Prevention of hypokalemia
requires particular attention in the following conditions: patients receiving digitalis and diuretics
for congestive heart failure, hepatic cirrhosis and ascites, states of aldosterone excess with
NDA 18225/S-024
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normal renal function, potassium-losing nephropathy, certain diarrheal states, or other states
where hypokalemia is thought to represent particular added risks to the patient, i.e., history of
ventricular arrhythmias.
In patients with hepatic cirrhosis and ascites, sudden alterations of electrolyte balance may
precipitate hepatic encephalopathy and coma. Treatment in such patients is best initiated in the
hospital with small doses and careful monitoring of the patient's clinical status and electrolyte
balance. Supplemental potassium and/or spironolactone may prevent hypokalemia and
metabolic alkalosis in these patients.
Ototoxicity
In cats, dogs and guinea pigs, bumetanide has been shown to produce ototoxicity. In these test
animals bumetanide was 5 to 6 times more potent than furosemide and, since the diuretic potency
of bumetanide is about 40 to 60 times furosemide, it is anticipated that blood levels necessary to
produce ototoxicity will rarely be achieved. The potential exists, however, and must be
considered a risk of intravenous therapy, especially at high doses, repeated frequently in the face
of renal excretory function impairment. Potentiation of aminoglycoside ototoxicity has not been
tested for bumetanide. Like other members of this class of diuretics, bumetanide probably shares
this risk.
Allergy to Sulfonamides
Patients allergic to sulfonamides may show hypersensitivity to Bumex.
Thrombocytopenia
Since there have been rare spontaneous reports of thrombocytopenia from postmarketing
experience, patients should be observed regularly for possible occurrence of thrombocytopenia.
PRECAUTIONS
General
Serum potassium should be measured periodically and potassium supplements or potassium
sparing diuretics added if necessary. Periodic determinations of other electrolytes are advised in
patients treated with high doses or for prolonged periods, particularly in those on low-salt diets.
Hyperuricemia may occur; it has been asymptomatic in cases reported to date. Reversible
elevations of the BUN and creatinine may also occur, especially in association with dehydration
and particularly in patients with renal insufficiency. Bumex may increase urinary calcium
excretion with resultant hypocalcemia.
Diuretics have been shown to increase the urinary excretion of magnesium; this may result in
hypomagnesemia.
Laboratory Tests
Studies in normal subjects receiving Bumex revealed no adverse effects on glucose tolerance,
plasma insulin, glucagon and growth hormone levels, but the possibility of an effect on glucose
NDA 18225/S-024
Page 7
metabolism exists. Periodic determinations of blood sugar should be done, particularly in
patients with diabetes or suspected latent diabetes.
Patients under treatment should be observed regularly for possible occurrence of blood
dyscrasias, liver damage or idiosyncratic reactions, which have been reported occasionally in
foreign marketing experience. The relationship of these occurrences to Bumex use is not certain.
Drug Interactions
Drugs With Ototoxic Potential (see WARNINGS)
Especially in the presence of impaired renal function, the use of parenterally administered
bumetanide in patients to whom aminoglycoside antibiotics are also being given should be
avoided, except in life-threatening conditions.
Drugs With Nephrotoxic Potential
There has been no experience with the concurrent use of Bumex with drugs known to have a
nephrotoxic potential. Therefore, the simultaneous administration of these drugs should be
avoided.
Lithium
Lithium should generally not be given with diuretics (such as Bumex) because they reduce its
renal clearance and add a high risk of lithium toxicity.
Probenecid
Pretreatment with probenecid reduces both the natriuresis and hyperreninemia produced by
Bumex. This antagonistic effect of probenecid on Bumex natriuresis is not due to a direct action
on sodium excretion but is probably secondary to its inhibitory effect on renal tubular secretion
of bumetanide. Thus, probenecid should not be administered concurrently with Bumex.
Indomethacin
Indomethacin blunts the increases in urine volume and sodium excretion seen during Bumex
treatment and inhibits the bumetanide-induced increase in plasma renin activity. Concurrent
therapy with Bumex is thus not recommended.
Antihypertensives
Bumex may potentiate the effect of various antihypertensive drugs, necessitating a reduction in
the dosage of these drugs.
Digoxin
Interaction studies in humans have shown no effect on digoxin blood levels.
Anticoagulants
Interaction studies in humans have shown Bumex to have no effect on warfarin metabolism or on
plasma prothrombin activity.
NDA 18225/S-024
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Carcinogenesis, Mutagenesis and Impairment of Fertility
Bumex was devoid of mutagenic activity in various strains of Salmonella typhimurium when
tested in the presence or absence of an in vitro metabolic activation system. An 18-month study
showed an increase in mammary adenomas of questionable significance in female rats receiving
oral doses of 60 mg/kg/day (2000 times a 2-mg human dose). A repeat study at the same doses
failed to duplicate this finding.
Reproduction studies were performed to evaluate general reproductive performance and fertility
in rats at oral dose levels of 10, 30, 60 or 100 mg/kg/day. The pregnancy rate was slightly
decreased in the treated animals; however, the differences were small and not statistically
significant.
Pregnancy
Teratogenic Effects
Pregnancy Category C. Bumex is neither teratogenic nor embryocidal in mice when given in
doses up to 3400 times the maximum human therapeutic dose.
Bumex has been shown to be nonteratogenic, but it has a slight embryocidal effect in rats when
given in doses of 3400 times the maximum human therapeutic dose and in rabbits at doses of 3.4
times the maximum human therapeutic dose. In one study, moderate growth retardation and
increased incidence of delayed ossification of sternebrae were observed in rats at oral doses of
100 mg/kg/day, 3400 times the maximum human therapeutic dose. These effects were
associated with maternal weight reductions noted during dosing. No such adverse effects were
observed at 30 mg/kg/day (1000 times the maximum human therapeutic dose). No fetotoxicity
was observed at 1000 to 2000 times the human therapeutic dose.
In rabbits, a dose-related decrease in litter size and an increase in resorption rate were noted at
oral doses of 0.1 and 0.3 mg/kg/day (3.4 and 10 times the maximum human therapeutic dose). A
slightly increased incidence of delayed ossification of sternebrae occurred at 0.3 mg/kg/day;
however, no such adverse effects were observed at the dose of 0.03 mg/kg/day. The sensitivity
of the rabbit to Bumex parallels the marked pharmacologic and toxicologic effects of the drug in
this species.
Bumex was not teratogenic in the hamster at an oral dose of 0.5 mg/kg/day (17 times the
maximum human therapeutic dose). Bumetanide was not teratogenic when given intravenously
to mice and rats at doses up to 140 times the maximum human therapeutic dose.
There are no adequate and well-controlled studies in pregnant women. A small investigational
experience in the United States and marketing experience in other countries to date have not
indicated any evidence of adverse effects on the fetus, but these data do not rule out the
possibility of harmful effects. Bumex should be given to a pregnant woman only if the potential
benefit justifies the potential risk to the fetus.
NDA 18225/S-024
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Nursing Mothers
It is not known whether this drug is excreted in human milk. As a general rule, nursing should
not be undertaken while the patient is on Bumex since it may be excreted in human milk.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 18 have not been established.
In vitro studies using pooled sera from critically ill neonates have shown bumetanide to be a
potent displacer of bilirubin (see CLINICAL PHARMACOLOGY: Pediatric Pharmacology).
The administration of bumetanide could present a particular concern if given to critically ill or
jaundiced neonates at risk for kernicterus.
Geriatric Use
Clinical studies of Bumex did not include sufficient numbers of subjects aged 65 and over to
determine whether they responded differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
ADVERSE REACTIONS
The most frequent clinical adverse reactions considered probably or possibly related to Bumex
are muscle cramps (seen in 1.1% of treated patients), dizziness (1.1%), hypotension (0.8%),
headache (0.6%), nausea (0.6%) and encephalopathy (in patients with preexisting liver disease)
(0.6%). One or more of these adverse reactions have been reported in approximately 4.1% of
patients treated with Bumex.
Serious skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been
reported in association with bumetanide use.
Less frequent clinical adverse reactions to Bumex are impaired hearing (0.5%), pruritus (0.4%),
electrocardiogram changes (0.4%), weakness (0.2%), hives (0.2%), abdominal pain (0.2%),
arthritic pain (0.2%), musculoskeletal pain (0.2%), rash (0.2%) and vomiting (0.2%). One or
more of these adverse reactions have been reported in approximately 2.9% of patients treated
with Bumex.
Other clinical adverse reactions, which have each occurred in approximately 0.1% of patients,
are vertigo, chest pain, ear discomfort, fatigue, dehydration, sweating, hyperventilation, dry
mouth, upset stomach, renal failure, asterixis, itching, nipple tenderness, diarrhea, premature
ejaculation and difficulty maintaining an erection.
NDA 18225/S-024
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Laboratory abnormalities reported have included hyperuricemia (in 18.4% of patients tested),
hypochloremia (14.9%), hypokalemia (14.7%), azotemia (10.6%), hyponatremia (9.2%),
increased serum creatinine (7.4%), hyperglycemia (6.6%), and variations in phosphorus (4.5%),
CO content (4.3%), bicarbonate (3.1%) and calcium (2.4%). Although manifestations of the
pharmacologic action of Bumex, these conditions may become more pronounced by intensive
therapy.
Also reported have been thrombocytopenia (0.2%) and deviations in hemoglobin (0.8%),
prothrombin time (0.8%), hematocrit (0.6%), WBC (0.3%) and differential counts (0.1%). There
have been rare spontaneous reports of thrombocytopenia from postmarketing experience.
Diuresis induced by Bumex may also rarely be accompanied by changes in LDH (1.0%), total
serum bilirubin (0.8%), serum proteins (0.7%), SGOT (0.6%), SGPT (0.5%), alkaline
phosphatase (0.4%), cholesterol (0.4%) and creatinine clearance (0.3%). Increases in urinary
glucose (0.7%) and urinary protein (0.3%) have also been seen.
OVERDOSAGE
Overdosage can lead to acute profound water loss, volume and electrolyte depletion,
dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular
thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness,
mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement
of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum
electrolyte levels.
DOSAGE AND ADMINISTRATION
Dosage should be individualized with careful monitoring of patient response.
Oral Administration
The usual total daily dosage of Bumex is 0.5 mg to 2 mg and in most patients is given as a single
dose.
If the diuretic response to an initial dose of Bumex is not adequate, in view of its rapid onset and
short duration of action, a second or third dose may be given at 4- to 5-hour intervals up to a
maximum daily dose of 10 mg. An intermittent dose schedule, whereby Bumex is given on
alternate days or for 3 to 4 days with rest periods of 1 to 2 days in between, is recommended as
the safest and most effective method for the continued control of edema. In patients with hepatic
failure, the dosage should be kept to a minimum and, if necessary, dosage increased very
carefully.
Because cross-sensitivity with furosemide has rarely been observed, Bumex can be substituted at
approximately a 1:40 ratio of Bumex to furosemide in patients allergic to furosemide.
Parenteral Administration
Bumetanide injection may be administered parenterally (IV or IM) to patients in whom
gastrointestinal absorption may be impaired or in whom oral administration is not practical.
NDA 18225/S-024
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Parenteral treatment should be terminated and oral treatment instituted as soon as possible.
HOW SUPPLIED
Tablets, 0.5 mg (light green), bottles of 100 (NDC 0004-0125-01) and 5000 (NDC 0004-0125
11); 1 mg (yellow), bottles of 100 (NDC 0004-0121-01), 500 (NDC 0004-0121-14) and 5000
(NDC 0004-0121-11); 2 mg (peach), bottles of 100 (NDC 0004-0162-01) and 5000 (NDC 0004
0162-11).
Imprint on tablets: 0.5 mg–ROCHE BUMEX 0.5; 1 mg–ROCHE BUMEX 1; 2 mg–ROCHE
BUMEX 2.
Store tablets at 59° to 86°F (15° to 30°C).
Validus Pharmaceuticals LLC
19 Cherry Hill Road, Suite 310
Parsippany, NJ 07054
1-866-9VALIDUS
(1-866-982-5438)
info@validuspharma.com
© 2008 Validus Pharmaceuticals LLC
090901
(Rev 9/2009)
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HALOG-E CREAM
(Halcinonide Cream, USP) 0.1%
For Topical Use Only.
Not For Ophthalmic Use.
DESCRIPTION
The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-
inflammatory and antipruritic agents. The steroids in this class include halcinonide.
Halcinonide is designated chemically as 21-Chloro-9-fluoro-11β,16α, 17-trihydroxy-
pregn-4-ene-3,20-dione cyclic 16,17-acetal with acetone. Graphic formula:
C24H32ClFO5, MW 454.96, CAS-3093-35-4
Each gram of 0.1% HALOG-E CREAM (Halcinonide Cream, USP) contains 1 mg
halcinonide in a hydrophilic vanishing cream base consisting of castor oil, ceteareth-20
(and) cetearyl alcohol, dimethicone 350, propylene glycol, propylene glycol stearate,
purified water, and white petrolatum. This formulation is water-washable, greaseless, and
nonstaining, with moisturizing and emollient properties.
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions.
The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear.
Various laboratory methods, including vasoconstrictor assays, are used to compare and
predict potencies and/or clinical efficacies of the topical corticosteroids. There is some
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
evidence to suggest that a recognizable correlation exists between vasoconstrictor
potency and therapeutic efficacy in man.
Pharmacokinetics
The extent of percutaneous absorption of topical corticosteroids is determined by many
factors including the vehicle, the integrity of the epidermal barrier, and the use of
occlusive dressings.
Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or
other disease processes in the skin increase percutaneous absorption. Occlusive dressings
substantially increase the percutaneous absorption of topical corticosteroids. Thus,
occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant
dermatoses (see DOSAGE AND ADMINISTRATION).
Once absorbed through the skin, topical corticosteroids are handled through
pharmacokinetic pathways similar to systemically administered corticosteroids.
Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are
metabolized primarily in the liver and are then excreted by the kidneys. Some of the
topical corticosteroids and their metabolites are also excreted into the bile.
INDICATIONS AND USAGE
HALOG-E CREAM (Halcinonide Cream, USP) 0.1% is indicated for the relief of the
inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
CONTRAINDICATIONS
Topical corticosteroids are contraindicated in those patients with a history of hyper-
sensitivity to any of the components of the preparations.
PRECAUTIONS
General
Systemic absorption of topical corticosteroids has produced reversible hypothalamic-
pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome,
hyperglycemia, and glucosuria in some patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Conditions which augment systemic absorption include the application of the more potent
steroids, use over large surface areas, prolonged use, and the addition of occlusive
dressings.
Therefore, patients receiving a large dose of any potent topical steroid applied to a large
surface area or under an occlusive dressing should be evaluated periodically for evidence
of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests,
and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the
body temperature occurs, an attempt should be made to withdraw the drug, to reduce the
frequency of application, substitute a less potent steroid, or use a sequential approach
when utilizing the occlusive technique.
Recovery of HPA axis function and thermal homeostasis are generally prompt and
complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid
withdrawal may occur, requiring supplemental systemic corticosteroids. Occasionally, a
patient may develop a sensitivity reaction to a particular occlusive dressing material or
adhesive and a substitute material may be necessary.
Children may absorb proportionally larger amounts of topical corticosteroids and thus be
more susceptible to systemic toxicity (see PRECAUTIONS: Pediatric Use).
If irritation develops, topical corticosteroids should be discontinued and appropriate
therapy instituted.
In the presence of dermatological infections, the use of an appropriate antifungal or
antibacterial agent should be instituted. If a favorable response does not occur promptly,
the corticosteroid should be discontinued until the infection has been adequately
controlled.
This preparation is not for ophthalmic use.
Information for the Patient
Patients using topical corticosteroids should receive the following information and
instructions:
1) This medication is to be used as directed by the physician. It is for dermatologic use
only. Avoid contact with the eyes.
2) Patients should be advised not to use this medication for any disorder other than for
which it was prescribed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
3) The treated skin area should not be bandaged or otherwise covered or wrapped as to
be occlusive unless directed by the physician.
4) Patients should report any signs of local adverse reactions especially under occlusive
dressing.
5) Parents of pediatric patients should be advised not to use tight-fitting diapers or
plastic pants on a child being treated in the diaper area, as these garments may
constitute occlusive dressings.
Laboratory Tests
A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating HPA
axis suppression.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential
or the effect on fertility of topical corticosteroids.
Studies to determine mutagenicity with prednisolone and hydrocortisone showed
negative results.
Pregnancy
Teratogenic Effects: Category C
Corticosteroids are generally teratogenic in laboratory animals when administered
systemically at relatively low dosage levels. The more potent corticosteroids have been
shown to be teratogenic after dermal application in laboratory animals. There are no
adequate and well-controlled studies in pregnant women on teratogenic effects from
topically applied corticosteroids. Therefore, topical corticosteroids should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of
this class should not be used extensively on pregnant patients, in large amounts, or for
prolonged periods of time.
Nursing Mothers
It is not known whether topical administration of corticosteroids could result in sufficient
systemic absorption to produce detectable quantities in breast milk. Systemically
administered corticosteroids are secreted into breast milk in quantities not likely to have
a deleterious effect on the infant. Nevertheless, caution should be exercised when topical
corticosteroids are administered to a nursing woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Pediatric Use
Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-
induced HPA axis suppression and Cushing’s syndrome than mature patients
because of a larger skin surface area to body weight ratio.
HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been
reported in children receiving topical corticosteroids. Manifestations of adrenal
suppression in children include linear growth retardation, delayed weight gain, low
plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of
intracranial hypertension include bulging fontanelles, headaches, and bilateral
papilledema.
Administration of topical corticosteroids to children should be limited to the least amount
compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may
interfere with the growth and development of children.
Geriatric Use
Of approximately 1000 patients included in clinical studies of 0.1% HALOG-E CREAM,
12% were 60 years or older, while 4% were 70 years or older. No overall differences in
safety were observed between these patients and younger patients. Efficacy data have not
been evaluated for differences between elderly and younger patients. Other reported
clinical experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS
The following local adverse reactions are reported infrequently with topical
corticosteroids, but may occur more frequently with the use of occlusive dressings
(reactions are listed in an approximate decreasing order of occurrence): burning, itching,
irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation,
perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary
infection, skin atrophy, striae, and miliaria.
OVERDOSAGE
Topically applied corticosteroids can be absorbed in sufficient amounts to produce
systemic effects (see PRECAUTIONS: General).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
DOSAGE AND ADMINISTRATION
Apply HALOG-E CREAM (Halcinonide Cream, USP) 0.1% to the affected area one to
three times daily. Rub in gently.
Occlusive Dressing Technique
Occlusive dressings may be used for the management of psoriasis or other recalcitrant
conditions. Gently rub a small amount of cream into the lesion until it disappears.
Reapply the preparation leaving a thin coating on the lesion, cover with a pliable
nonporous film, and seal the edges. If needed, additional moisture may be provided by
covering the lesion with a dampened clean cotton cloth before the nonporous film is
applied or by briefly wetting the affected area with water immediately prior to applying
the medication. The frequency of changing dressings is best determined on an individual
basis. It may be convenient to apply HALOG-E CREAM under an occlusive dressing in
the evening and to remove the dressing in the morning (i.e., 12-hour occlusion). When
utilizing the 12-hour occlusion regimen, additional cream should be applied, without
occlusion, during the day. Reapplication is essential at each dressing change.
If an infection develops, the use of occlusive dressings should be discontinued and
appropriate antimicrobial therapy instituted.
HOW SUPPLIED
HALOG-E® CREAM (Halcinonide Cream, USP) 0.1% is supplied as tubes containing
30 g (NDC 0003-1494-21) and 60 g (NDC 0003-1494-31) of cream.
Storage
Store at room temperature; avoid freezing and refrigeration.
Westwood-Squibb Pharmaceuticals, Inc.
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
J4102D
1077519A2
Revised April 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:39.885606
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18234s020lbl.pdf', 'application_number': 18234, 'submission_type': 'SUPPL ', 'submission_number': 20}
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